CN101378746B - 苯并稠合杂环磺酰胺衍生物在制备治疗疼痛的药物中的应用 - Google Patents
苯并稠合杂环磺酰胺衍生物在制备治疗疼痛的药物中的应用 Download PDFInfo
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- CN101378746B CN101378746B CN2006800530302A CN200680053030A CN101378746B CN 101378746 B CN101378746 B CN 101378746B CN 2006800530302 A CN2006800530302 A CN 2006800530302A CN 200680053030 A CN200680053030 A CN 200680053030A CN 101378746 B CN101378746 B CN 101378746B
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Abstract
本发明是治疗疼痛的方法,包括对有此需要的患者施用治疗有效量的一种或多种如本文式(I)和式(II)所示的新苯并稠合杂环磺酰胺衍生物。本发明还涉及治疗疼痛的多种方法,包括使用镇痛药和本文所述的式(I)和式(II)化合物共同治疗。
Description
与相关申请的交叉参照
本申请要求申请日为2005年12月19日的美国临时申请60/751,686和申请日为2006年2月15的美国临时申请60/773,812的权益,这两篇申请文献均以引用的方式被全文引入本文。
发明领域
本发明涉及苯并稠合杂环磺酰胺衍生物用于治疗急性、慢性、炎症性和/或神经性疼痛的应用。
发明背景
疼痛通常被定义为令人不愉快的感觉和情绪体验,同时伴随事实上或潜在的组织损伤(Wileman L,Advances in pain management,Scrip Report,2000)。
急性疼痛是一种对于不利的化学、热量或机械刺激的生理学反应,其可能与外科手术、创伤或急症相随。这些状况包括但不限于术后痛、运动医学损伤、腕管综合症、烧伤、肌肉骨骼扭伤和劳损、肌腱劳损、颈臂疼痛综合症、消化不良、胃溃疡、十二指肠溃疡、肾结石疼痛、胆囊痛、胆结石疼痛、痛经、子宫内膜异位、生产疼痛、风湿疼痛、头痛或牙痛。
慢性疼痛是一种超出正常损伤或疾病的原因的疼痛状况,其可能是炎症或严重累积的疼痛疾病阶段的后果。各种类型的慢性疼痛包括但不限于头痛、偏头痛、三叉神经痛、颞下颌关节综合症、纤维肌痛综合症、骨关节炎、类风湿性关节炎、由骨关节炎、骨质疏松、骨转移或其它未知原因引起的骨痛、痛风、纤维组织炎、肌筋膜痛、胸廓出口综合症、上背部痛或下腰痛(其中背部疼痛由全身性、局部性或原始脊柱疾病(神经根病)引起)、骨盆痛、心脏性胸痛、非心脏性胸痛、脊髓损伤相关性疼痛、中枢性中风后疼痛、癌症痛、AIDS痛、镰状细胞痛或老年痛。
神经性疼痛被定义为在外周或中枢神经系统中由异常躯体感觉处理引起的疼痛,包括疼痛性糖尿病性周围神经病变、疱疹后神经痛、三叉神经痛、中风后疼痛、多样性硬化症相关性疼痛、神经病相关性疼痛例如原发性或创伤后神经病和单神经炎、HIV-相关性神经性疼痛、癌症相关性神经性疼痛、腕管相关性神经性疼痛、脊髓损伤相关性疼痛、络合区域性疼痛综合症、纤维肌痛相关性神经性疼痛、腰部和颈部疼痛、反射性交感神经营养不良、幻肢综合症和其他的慢性和虚症相关性疼痛综合症。
现在仍需提供有效治疗疼痛的方法。
发明概述
本发明涉及治疗疼痛的方法,包括对有此需要的患者施用治疗有效量的式(I)化合物
其中
R1和R2独立地选自氢和低级烷基;
R4选自氢和低级烷基;
a是1-2的整数;
其中b是0-4的整数;以及其中c是0-2的整数;
每一个R5独立地选自卤素、低级烷基和硝基;
那么a是1;
或其药学上可接受的盐。
本发明还涉及治疗疼痛的方法,包括对有此需要的患者施用治疗有效量的式(II)化合物
或其药学可接受的盐。
本发明的一个例子是治疗疼痛的方法,其中所述疼痛选自急性疼痛或慢性疼痛,包括对有此需要的患者施用治疗有效量的任何上述化合物或药物组合物。
本发明的另一个例子是治疗疼痛的方法,其中所述疼痛是炎症性疼痛,包括对有此需要的患者施用治疗有效量的任何上述化合物或药物组合物。
本发明的另一个例子是治疗疼痛的方法,其中所述疼痛是神经性疼痛,包括对有此需要的患者施用治疗有效量的任何上述化合物或药物组合物。
本发明还涉及治疗疼痛的方法,包括对有此需要的患者施用至少一种止痛药和上文所述的式(I)或式(II)化合物以共同治疗。
发明详述
本发明涉及治疗疼痛的方法,包括对有此需要的患者施用治疗有效量的式(I)化合物
或其药学可接受的盐,其中 a、R1、R2和R4如上文所定义。本发明还涉及治疗疼痛的方法,包括使用至少一种止痛药和上文所述的式(I)或式(II)化合物共同治疗。
如本文所述,术语“疼痛”被定义为包括急性、慢性、炎症性和神经 性疼痛(优选糖尿病神经病变)。另外,疼痛可能是中枢神经介导的或外周神经介导的,由结构组织损伤、软组织损伤或进行性疾病造成。任何与中枢神经介导的、外周神经介导的、结构组织损伤、软组织损伤或进行性疾病相关的疼痛都可能是急性或慢性的。
如本文所述,除非另有说明,疼痛包括炎症性疼痛、中枢神经介导的疼痛、外周神经介导的疼痛、内脏痛、组织相关痛、癌症痛、软组织损伤相关性疼痛、进行性疾病相关性疼痛、神经性疼痛、急性损伤造成的急性痛、创伤造成的急性痛、外科手术造成的急性痛、头痛、牙痛、背痛(优选下腰痛)、神经症状造成的慢性痛和中风后症状造成的慢性痛。
本发明的一个实施方案是治疗疼痛的方法,其中疼痛是急性痛。本发明的另一个实施方案是治疗疼痛的方法,其中疼痛是慢性痛。本发明的另一个实施方案是治疗疼痛的方法,其中疼痛是神经性痛,更优选糖尿病性神经病。本发明的另一个实施方案是治疗疼痛的方法,其中疼痛是炎症性痛。
在一个实施方案中,疼痛选自骨关节炎、类风湿性关节炎、纤维肌痛、头痛、牙痛、烧伤、晒伤、动物咬伤(例如狗咬伤、猫咬伤、蛇咬伤、蜘蛛咬伤、昆虫蛰伤,等等)、神经原性膀胱、良性前列腺肥大、间质性膀胱炎、鼻炎、接触性皮炎/超敏反应、搔痒、湿疹、咽炎、粘膜炎、肠炎、蜂窝组织炎、灼痛、坐骨神经炎、下颌关节神经痛、末梢神经炎、多发性神经炎、残肢痛、幻肢痛、术后肠梗阻、胆囊炎、乳腺切除后疼痛综合症、口腔神经性疼痛、夏科氏疼痛、反射性交感神经营养不良、格林-巴利综合症、感觉异常性股痛、烧伤口部综合症、疱疹后神经痛、三叉神经痛、外周神经病、两侧外周神经病、糖尿病性神经病、带状疱疹后神经痛、三叉神经痛、视神经炎、发热后神经炎、游走性神经炎、节段性神经炎、贡博(氏)神经炎、神经元炎、颈臂神经痛、脑神经痛、膝状节神经痛、舌咽(glossopharyngial)神经痛、偏头痛性神经痛、特发性神经痛、肋间神经痛、乳腺内神经痛、摩顿(氏)神经痛、鼻睫神经痛、枕神经痛、红斑性肢痛病、斯路德(氏)神经痛、蝶腭(splenopalatine)神经痛、眶上神经痛、翼管神经痛、炎性肠病、过敏性肠综合症、劳动、分娩、经期痉挛、癌症、背痛、下腰痛和腕管综合症疼痛。
急性疼痛包括由急性损伤、创伤、疾病或外科手术(例如胸外科手术(包括心脏直视或旁路手术))引起的疼痛。急性疼痛还包括但不限于头痛、术后痛、肾结石疼痛、胆囊痛、胆结石疼痛、产科疼痛、风湿病疼痛、牙痛或有下述原因造成的疼痛:运动医学损伤、腕管综合症、烧伤、肌与骨骼扭伤和劳损、肌腱劳损、颈臂疼痛综合症、消化不良、胃溃疡、十二指肠溃疡、痛经或子宫内膜异位症。
慢性疼痛包括由炎性症状、骨关节炎、类风湿性关节炎或疾病的后遗症、急性损伤或创伤引起的疼痛。慢性疼痛还包括但不限于头痛、上背部或下腰痛(选自由全身性、局部性或原发性脊柱疾病(选自神经根病)引起的背部疼痛)、骨痛(选自由骨关节炎、骨质疏松、骨转移或未知原因引起的骨痛)、骨盆痛、脊髓损伤相关性疼痛、心脏性胸痛、非心脏性胸痛、中枢性中风后疼痛、肌筋膜痛、癌症疼痛、AIDS痛、镰状细胞痛、老年痛或有下述原因引起的疼痛:头痛、偏头痛、三叉神经痛、颞下颌关节综合症、纤维肌痛综合症、骨关节炎、类风湿性关节炎、痛风、纤维组织炎或胸廓出口综合症。
神经性疼痛包括由慢性或虚弱症状或疾病引起的疼痛。能够引起神经性疼痛的慢性或虚弱症状或疾病包括但不限于疼痛性糖尿病性周围神经病变、疱疹后神经痛、三叉神经痛、中风后疼痛、多样硬化症相关性疼痛、神经病相关性疼痛例如原发性或创伤后神经病和单神经炎、HIV-相关性神经性疼痛、癌症相关性神经性疼痛、腕管相关性神经性疼痛、脊髓损伤相关性疼痛、络合区域性疼痛综合症、纤维肌痛相关性神经性疼痛、腰部和颈部疼痛、反射性交感神经营养不良、幻肢综合症和其他慢性和虚弱症状相关性疼痛综合症。
在本文中,术语“止痛药”是指能够减轻疼痛的任何药物试剂,包括但不限于阿片类物质及其衍生物、非类固醇类抗炎药、对乙酰氨基酚类化合物、NO供体化合物、TRAMADOL和TRAMADOL样化合物和抗抑郁药例如阿米曲替林。优选的镇痛药是曲马朵或Tylenol。
适当的例子包括但不限于对乙酰氨基酚、盐酸阿芬他尼、氨苯甲酸钾、氨苯甲酸钠、阿尼多昔、阿尼利定、盐酸阿尼利定、盐酸阿尼洛泮、阿尼罗酸、安替比林、阿司匹林、苯噁洛芬、盐酸苄达明、盐酸比西发定、盐酸布芬太尼、马来酸溴朵林、溴芬酸钠、盐酸丁丙诺啡、布他西丁、布替西雷、布托啡诺、酒石酸布托啡诺、卡马西平、 卡巴匹林钙、盐酸卡必芬、柠檬酸卡芬太尼、琥珀酸环丙法多、西拉马朵、盐酸西拉马朵、氯尼塞利、氯尼辛、可待因、磷酸可待因、硫酸可待因、盐酸考诺封(Conorphone)、环唑辛、盐酸右奥沙屈、右培美酸、地佐辛、双氟尼柳、酸性酒石酸二氢可待因、二甲法登、安乃近、盐酸多匹可明、氨甲茚酮、盐酸依那多林、依匹唑、酒石酸麦角胺、盐酸依托沙秦、依托芬那酯、丁香酚、非诺洛芬、非诺洛芬钙、柠檬酸芬太尼、夫洛非宁、氟苯柳、氟尼辛、氟尼辛甲葡胺、马来酸氟吡汀、氟丙喹宗、盐酸氟朵林、氟比洛芬、氢化吗啡酮、异丁芬酸、吲哚洛芬、酮佐辛、酮啡诺、酮咯酸氨丁三醇、盐酸来替米特、左醋美沙朵、盐酸左醋美沙朵、左南曲朵、酒石酸左啡诺、盐酸洛非咪唑、草酸洛芬太尼、洛西那朵、Lomoxicam、水杨酸镁、甲芬那酸、盐酸美大麻坦、盐酸哌替啶、盐酸美普他酚、盐酸美沙酮、乙酸美沙朵、甲氧夫啉、左美丙嗪、乙酰美克法胺、盐酸米姆本、盐酸米芬太尼、吗林那宗、硫酸吗啡、莫沙佐、盐酸大麻坦、盐酸纳布啡、盐酸纳美酮、纳莫雷特、盐酸南曲朵、萘普生、萘普生钠、萘普索、盐酸奈福泮、盐酸奈西利定、盐酸诺美沙朵、盐酸奥芬太尼、奥他酰胺、奥伐尼、富马酸奥昔托隆、羟考酮、盐酸羟考酮、对苯二酸羟考酮、盐酸羟吗啡酮、培美酸、戊吗酮、喷他佐辛、盐酸喷他佐辛、乳酸喷他佐辛、盐酸非那吡啶、盐酸非尼拉朵、盐酸哌西那朵、匹那朵林、吡非尼酮、吡罗昔康乙醇胺、马来酸普拉多林、盐酸普地利定、盐酸普罗法朵、延胡索酸Propirarn、盐酸丙氧芬、萘磺酸丙氧芬、普罗沙唑、柠檬酸普罗沙唑、酒石酸普罗啡烷、盐酸吡咯利芬、盐酸瑞芬太尼、柳胆来司、马来酸沙乙酰胺、水杨酰胺、水杨酸甲葡胺、双水杨酯、水杨酸钠、甲磺酸螺朵林、舒芬太尼、柠檬酸舒芬太尼、他美辛、他尼氟酯、他洛柳酯、琥珀酸他扎朵林、特丁非隆、四氢甲吲胺、替呋酸钠、盐酸替立定、硫平酸、甲磺酸托那佐辛、盐酸曲马多、盐酸曲芬太尼、三乙醇胺、盐酸维拉朵林、盐酸维立洛泮、伏拉佐辛、甲磺酸佐尔啡诺、盐酸塞拉嗪、甲磺酸泽来索兴、佐美酸钠和珠卡赛辛。
另外,止痛药可以是组合产品,包括但不限于Novartis的FIORICET或Forests的ESGIC等(对乙酰氨基酚、布他比妥和咖啡因的组合)、FIORINAL等(阿司匹林、布他比妥和咖啡因的组合,Novartis)、MIGPRIV等(阿司匹林和metoclopromide的组合;Sanofi-Synthelabo)、 MIDRIN/MIDRID等(对乙酰氨基酚和氯醛比林的组合;Carnick)、Sanofi-Synthelabo的PARAMAX或Dolorgiet的MIGRAENERTON等(对乙酰氨基酚和甲氧氯普胺的组合)、Abbott的VICODIN等(对乙酰氨基酚和氢可酮的组合)、STADOL NS(布托啡诺鼻腔喷雾;Bristol-MyersSquibb)、Boehringer Ingelheim的LONARID或Pfizer的MIGRALEVE等(对乙酰氨基酚和可待因的组合),等等。
本文中,术语“患者”是指作为治疗、观察或试验对象的动物,优选哺乳动物,最优选人类。
本文中,术语“治疗有效量”是指活性化合物或药物制剂在组织系统、动物或人中被研究人员、兽医、医学博士或其他临床人员观察到的能够引起生物学或药学反应的量,所述反应包括被治疗的疾病或病症的症状有所减轻。
其中,本发明涉及共同治疗或联合治疗,包括施用一种或多种式(I)或式(II)化合物和一种或多种止痛药,“治疗有效量”是指药物联合应用的用量,在该用量下药物的联合作用能够产生所期望的生物或医学反应。例如,包括施用式(I)或式(II)化合物和至少一种止痛药的共同治疗的治疗有效量如下所述:当共同或相继使用时,式(I)或式(II)化合物的用量和止痛药的用量的并用效果能够起到治疗作用。另外,本领域技术人员可以理解的是,如上文举例所述,当以治疗有效量进行共同治疗时,单个式(I)或式(II)化合物的用量和/或单个止痛药的用量可能是或者可能不是治疗有效的。
在本文中,术语“共同治疗”和“联合治疗”是指施用一种或多种式(I)或式(II)化合物和一种或多种止痛药共同治疗有此需要的患者,其中式(I)或式(II)化合物和止痛药以任何适当的方式同时、相继、分开或者以单个药剂形式进行给药。当式(I)或式(II)化合物和止痛药以分开的剂型给药时,每种化合物每天的剂量可以相同或不同。式(I)或式(II)化合物和止痛药可通过相同或不同的给药途径进行给药。给药的适当方法的例子包括但不限于,口服、静脉注射(iv)、肌肉注射(im)、皮下注射(sc)、经皮给药和直肠给药。化合物还可以被直接给药至神经系统,包括但不限于大脑内、心室内、脑室内、膜内、池内、脊柱内和/或脊柱周围,给药途径为利用或不利用泵装置通过颅内或脊柱内注射针和/或导管进行递送。治疗期间,式(I)或式(II)化合物和止痛药可以同时以分开或同 一个制剂形式在相同或不同的时间同时或交替给药。
在本发明的一个实施方案中,R1选自氢和甲基。在本发明的另一个实施方案中,R2选自氢和甲基。在本发明另一个实施方案中,R1和R2均为氢或者R1和R2均为甲基。
在本发明一个实施方案中,-(CH2)a-选自-CH2-和-CH2-CH2-。在本发明的另一个实施方案中,-(CH2)a-是-CH2-。
本发明的一个实施方案中,R4选自氢和甲基,优选地,R4是氢。
在本发明的一个实施方案中,a是1。
在本发明的一个实施方案中,b是0-2的整数。在本发明的另一个实施方案中,c是0-2的整数。在本发明的另一个实施方案中,b是0-1的整数。在本发明的另一个实施方案中,c是0-1的整数。在本发明的另一个实施方案中,b和c的和是0-2的整数,优选是0-1的整数。在本发明的另一个实施方案中,b是0-2的整数,c是0。
在本发明的一个实施方案中, 选自2-(2,3-二氢-苯并[1,4]二氧杂环己烯基)、2-(苯并[1,3]二氧杂环戊烯基)、3-(3,4-二氢-苯并[1,4]二氧杂环庚烯基)、2-(6-氯-2,3-二氢-苯并[1,4]二氧杂环己烯基)、2-(6-氟-2,3-二氢-苯并[1,4]二氧杂环己烯基)、2-(色满基)、2-(5-氟-2,3-二氢-苯并[1,4]二氧杂环己烯基)、2-{7-氯-2,3-二氢-苯并[1,4]二氧杂环己烯基)、2-(6-氯-苯并[1,3]二氧杂环戊烯基)、2-(7-硝基-2,3-二氢-苯并[1,4]二氧杂环己烯基)、2-(7-甲基-2,3-二氢-苯并[1,4]-二氧杂环己烯基)、2-(5-氯-2,3-二氢-苯并[1,4]二氧杂环己烯基)、2-(6-溴-2,3-二氢-苯并[1,4]二氧杂环己烯基)、2-(6,7-二氯-2,3-二氢-苯并[1,4]二氧杂环己烯基)、2-(8-氯-2,3-二氢-苯并[1,4]二氧杂环己烯基)、2-(2,3-二氢-萘并[2,3-b][1,4]二氧杂环己烯基)和2-(4-甲基-苯并[1,3]二氧杂环戊烯基)。
在本发明的另一个实施方案中, 选自2-(苯并[1,3]二氧杂环戊烯基)、2-(2,3-二氢-苯并[1,4]二氧杂环己烯基)、2-(6-氯-2,3-二氢-苯并[1,4]二氧杂环己烯基)、2-(7-氯-2,3-二氢-苯并[1,4]二氧杂环己烯基)、2-(7-甲基-2,3-二氢-苯并[1,4]二氧杂环己烯基)、2-(6-溴-2,3-二氢-苯并[1,4]二氧杂环己烯基)和2-(6,7-二氯-2,3-二氢-苯并[1,4]二氧杂环己烯 基)。在本发明的另一个实施方案中, 选自2-(2,3-二氢-苯并[1,4]二氧杂环己烯基)、2-(7-甲基-2,3-二氢-苯并[1,4]二氧杂环己烯基)和2-(6-溴-2,3-二氢-苯并[1,4]二氧杂环己烯基)。
在本发明的一个实施方案中,R5选自卤素和低级烷基。本发明的另一个实施方案中,R5选自氯、氟、溴和甲基。
在本发明的一个实施方案中,式(I)化合物的立体中心是S-构型。在本发明的另一个实施方案中,式(I)化合物的立体中心是R-构型。
在本发明的一个实施方案中,式(I)化合物为对映体的富集混合物,其中%对映体富集浓度(%ee)大于约75%,优选大于约90%,更优选大于约95%,最优选大于约98%。
本发明的另一个实施方案包括如下所述物质,其中为一个或多个本文所述变量(即R1、R2、R3、R4、X-Y和A)选择的取代基可独立地选自本文所述列表的任何单个取代基或取代基的任何亚类。
本发明的代表性化合物列于下文表1。本发明其他的化合物列于表3。在下文表1和表2中,命名为“立体”的竖栏代表的是与标有星形符号的键相连接的杂环碳原子的立体构型。其中没有任何标示的,代表该化合物为立体构型的混合物。其中标有“R”或“S”的,代表对映体富集的起始原料的立体构型。
表1:式(I)的代表性化合物
表2:本发明的其他化合物
在本文中,除非另有说明,“卤素”是指氯、溴、氟和碘。
在本文中,除非另有说明,术语“烷基”不论是单独使用还是作为取代基的一部分,其包括直链和支链。例如,烷基包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲-丁基、叔-丁基、戊基等等。除非另有说明,当“低级”一词和烷基共同使用时,其代表碳链组成为1-4个碳原子。
在本文中,除非另有说明,“烷氧基”是指上述直链或支链烷基的残基上有氧原子。例如,甲氧基、乙氧基、正-丙氧基、仲-丁氧基、叔-丁氧基、正-己氧基等等。
在本文中,符号“*”是指立体中心。
当特定基团是“被取代”时(例如烷基、芳基等),此基团可有一个或多个取代基,优选1-5个取代基,更优选1-3个取代基,最优选1-2个取代基,独立地选自下述取代基列表。
对于取代基,术语“独立地”是指当可能存在超过一个这样的取代基时,所述取代基彼此可能是相同或不同的。
在本文所述的标准命名法中,先描述指定侧链末端部分,然后是与连接点邻近的官能团。因此,例如“苯基-烷基-氨基-羰基-烷基”取代基指的是下式基团:
说明书中的缩写,特别是线路图和实施例中的缩写如下所述:
DCC=二环己基碳二亚胺
DCE=二氯乙烷
DCM=二氯甲烷
DIPEA或DIEA=二异丙基乙基胺
DMF=N,N-二甲基甲酰胺
DMSO=二甲基亚砜
EDC=乙基碳二亚胺
Et3N或TEA=三乙胺
Et2O=-二乙醚
EA或EtOAc=乙酸乙酯
EtOH=乙醇
IPA=2-丙醇
Hept=庚烷
HOBT=1-羟基苯并三唑
HPLC=高压液相色谱法
LAH=氢化铝锂
M或MeOH=甲醇
NMR=核磁共振
Pd-C=钯载于碳的催化剂
RP HPLC=反相高压液相色谱法
RT或rt=室温
TEA=三乙胺
TFA=三氟乙酸
THF=四氢呋喃
TLC=薄层色谱法
如果本发明化合物具有至少一个手性中心,那么它们相应地以对映体形式存在。如果所述化合物具有两个或多个手性中心,它们还可以以非对映异构体形式存在。可以理解的是,所有的此类异构体及其混合物都被包括在本发明保护范围之内。另外,化合物的某些晶形以多晶形形式存在,并且这也包括在本发明保护范围之内。此外,某些化合物可与水或普通有机溶剂形成溶剂化物(即与水形成水合物),并且此溶剂化物被包括在本发明保护范围之内。
对于医学方面的应用,本发明化合物的盐指的是无毒性“药学可接受的盐”。然而,其他的盐可用于制备本发明化合物或其药学可接受的盐。本发明化合物适当的药学可接受的盐包括酸加成盐,此种盐可以例如,由本发明化合物溶液和药学可接受的酸溶液混合形成,所述酸例如是盐酸、硫酸、反丁烯二酸、马来酸、琥珀酸、醋酸、苯甲酸、柠檬酸、酒石酸、碳酸或磷酸。此外,如果本发明化合物中有酸的部分,其药学可接受的盐可以包括碱金属盐,例如钠或钾盐,碱土金属盐,例如钙或镁盐,和与适当的有机配体形成的盐,例如季铵盐。因此,典型的药学可接受的盐包括下述物质:
醋酸盐、苯磺酸盐、苯甲酸盐、碳酸氢盐、硫酸氢盐、酒石酸氢盐、硼酸盐、溴化物、依地酸钙、右旋樟脑磺酸、碳酸盐、氯化物、克拉维酸盐、柠檬酸盐、二氢氯化物、依地酸盐、乙二磺酸盐、丙酸酯十二烷基硫酸盐、乙磺酸盐、延胡索酸盐、葡庚糖酸盐、葡糖酸盐、 谷氨酸盐、乙醇酰阿散酸盐、己基间苯二酚酸盐、海巴、氢溴化物、氢氯化物、羟基萘甲酸盐、碘化物、异硫代硫酸盐、乳酸盐、乳糖酸盐、月桂酸盐、苹果酸盐、马来酸盐、扁桃酸盐、甲磺酸盐、甲基溴化物、甲基硝酸盐、甲基硫酸盐、粘酸盐、萘磺酸盐、硝酸盐、N-甲基葡萄糖胺盐、油酸盐、双羟萘酸盐(双羟萘酸盐)、棕榈酸盐、泛酸盐、磷酸盐/二磷酸盐、聚半乳糖醛酸盐、水杨酸盐、硬脂酸盐、硫酸盐、碱式醋酸盐、琥珀酸盐、鞣酸盐、酒石酸盐、8-氯茶碱盐、甲苯磺酸盐、三乙基碘化物和戊酸盐。
可用于制备药学可接受的盐的代表性酸和碱包括下述物质:酸包括乙酸、2,2-二氯乙酸、酰化氨基酸、脂肪酸、海藻酸、抗坏血酸、L-天冬氨酸、苯磺酸、苯甲酸、4-乙酰胺基苯甲酸、(+)-樟脑酸、樟脑磺酸、(+)-(1S)-樟脑-10-磺酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环拉酸、月桂基硫酸、乙烷-1,2-二磺酸、乙磺酸、2-羟基-乙烷磺酸、甲酸、反丁烯二酸、粘酸、龙胆酸、葡庚糖酸、D-葡糖酸、D-葡萄糖醛酸、L-谷氨酸、α-氧-戊二酸、羟乙酸、马尿酸、氢溴酸、盐酸、(+)-L-乳酸、(+-)-DL-乳酸、乳糖酸、马来酸、(-)-L-苹果酸、丙二酸、(+-)-DL-扁桃酸、甲磺酸、萘-2-磺酸、萘-1,5-二磺酸、1-羟基-2-萘甲酸、烟酸、硝酸、油酸、乳清酸、草酸、棕榈酸、双羟萘酸、磷酸、L-焦谷氨酸、水杨酸、4-氨基-水杨酸、癸二酸、硬脂酸、琥珀酸、硫酸、鞣酸、(+)-L-酒石酸、硫氰酸、p-甲苯磺酸和十一烯酸;和
碱包括铵、L-精氨酸、苯明、苄星、氢氧化钙、胆碱、地阿诺、二乙醇胺、二乙基胺、2-(二乙基氨基)-乙醇、乙醇胺、乙二胺、N-甲基-葡萄糖胺、海巴、1H-咪唑、L-赖氨酸、氢氧化镁、4-(2-羟基乙基)-吗啉、哌嗪、氢氧化钾、1-(2-羟基乙基)-吡咯烷、仲胺、氢氧化钠、三乙醇胺、氨丁三醇和氢氧化锌。
式(I)化合物可通过路线1所示方法制备得到:
路线1
相应地,式(X)的适当取代化合物,已知化合物或根据已知方法制备得到的化合物,与已知的磺酰胺化合物在有机溶剂例如THF、二氧六环等中反应,优选其中所述磺酰胺的用量为约2-5倍量,并且优选在温度为约50-100℃的温度下,更优选在大约回流温度进行反应,以得到相应的式(Ia)化合物。
任选地,式(X)的适当取代化合物、已知化合物或根据已知方法制备得到的化合物,与式(XI)的适当取代化合物、已知的或根据已知方法制得的化合物在碱例如TEA、DIPEA、吡啶等存在的条件下,在有机溶剂例如DMF、DMSO等中反应,生成相应的式(I)化合物。
路线2
相应地,式(XII)的适当取代化合物、已知化合物或根据已知方法(例如上述路线3所述)制备得到的化合物,与NH4OH、已知的化合物,任选地在有机溶剂例如乙腈等中反应,生成相应的式(XIII)化合物。
式(XIII)化合物与适当选择的还原剂例如LAH等在有机溶剂中反应,所述有机溶剂例如THF、二乙醚等,以生成相应的式(Xa)化合物。
路线3
相应地,式(XIV)的适当取代化合物,已知化合物或根据已知方法制备得到的化合物,与NH4OH在存在偶合剂例如DCC等条件下,任选地在有机溶剂例如乙腈等中反应,生成相应的式(XV)化合物。
式(XV)化合物与适当选择的还原剂例如LAH等在有机溶剂中反应,所述有机溶剂例如THF、二乙醚等,以生成相应的式(Xb)化合物。
路线4
相应地,式(XVI)的适当取代化合物、已知化合物或根据已知方法(例如,通过活化相应的其中J1为OH的化合物)制得的化合物,其中J1是适当的离去基团例如Br、Cl、I、甲苯磺酰基、甲磺酰、triflyl等,与氰化物例如氰化钾、氰化钠等在有机溶剂例如DMSO、DMF、THF等中反应,生成相应的式(XVII)化合物。
将式(XVII)化合物根据已知的方法还原,例如通过与适当的还原剂例如LAH、硼烷等反应,以生成相应的式(Xc)化合物。
路线5
相应地,根据已知方法活化式(XVIII)的适当取代化合物、已知化合物或根据已知方法制得的化合物,以生成相应的式(XIX)化合物,其中J2是适当的离去基团,例如甲苯磺酸盐、Cl、Br、I、甲磺酸盐、三甲磺酸盐等。
式(XIX)化合物与酞酰亚胺盐例如酞酰亚胺钾、酞酰亚胺钠等在有机溶剂例如DMF、DMSO、乙腈等中反应,优选在约50℃至约200℃,更优选在约回流温度下反应,以生成相应的式(XX)化合物。
式(XX)化合物与N2H4、已知化合物在有机溶剂例如乙醇、甲醇等中反应,优选在约50℃至约100℃,更优选在约回流温度下反应,以生成相应的式(Xd)化合物。
本领域技术人员还可以理解的是,如果想要式(X)化合物单个的对映体(或其中一种对映体被富集的对映体混合物),可以在进行上述路线1-5所述方法时通过取代相应的单一对映体(或其中一种对映体被富集的对映体混合物)作为适当的起始原料。
本领域技术人员可以理解的是,本发明的反应步骤可以在各种溶剂或溶剂系统中进行,所述反应步骤还可以在适当的溶剂或溶剂系统的混合物中进行。
如果制备本发明化合物的方法产生了立体异构体混合物,可采用常规技术例如制备色谱法分离这些异构体。制得的化合物可能是外消旋形式或者为单种的化合物。可通过合成特定对映体或者拆分制得对映体。例如,将化合物通过标准技术拆分为其对映体组份,例如与任选的活性酸成盐以生成非对映异构体对,然后分步结晶,再次生成游离碱,所述酸例如是(-)-二-p-甲苯酰-D-酒石酸和/或(+)-二-p-甲苯酰-L- 酒石酸。还可以将化合物拆分生成非对映异构体酯或酰胺,然后色谱分离,移除手性助剂。作为选择,可采用手性HPLC柱拆分化合物。
在制备本发明化合物的任一方法中,可能需要和/或想要保护所涉及的任何分子的敏感的或反应基团。可通过采用常规保护基团的方式达到上述目的,所述的保护基团例如是描述于Protective Groups inOrganic Chemistry中的那些物质ed.J.F.W.McOmie,Plenum Press,1973;和T.W.Greene & P.G.M.Wuts,Protective Groups in OrganicSynthesis.John Wiley & Sons,1991。保护基团可以在方便的后序阶段中以现有技术已知的方法进行去除。
本发明还包括药物组合物,其中包含一种或多种式(I)化合物和药学可接受的载体。包含一种或多种本发明化合物作为活性成分的药物组合物可通过下述方法制得:以常规的药物配料技术混合本发明化合物和药学可接受的载体。根据所需的给药途径(例如口服、胃肠外给药),载体可采用各种形式。因此,对于液体口服制剂,例如混悬液、酏剂和溶液,适当的载体和添加剂包括水、乙二醇、油、醇类、香料、防腐剂、稳定剂、着色剂等;对于固体口服制剂,例如粉末、胶囊和片剂,适当的载体和添加剂包括淀粉、糖、稀释剂、颗粒剂、润滑剂、粘合剂、崩解剂等。还可以对固体口服制剂进行包衣,包衣物质例如是糖或肠溶衣,以便调节吸收的主要部位。对于胃肠外给药,载体通常为无菌水,还可添加其他组分以增加溶解度或防腐性。注射性混悬液或溶液还可仅采用水性载体和适当的添加剂制得。
为了制备本发明药物组合物,作为活性成分的一种或多种本发明化合物与药学载体以常规的药物配料技术混合在一起,其中根据预期的给药制剂形式例如口服或胃肠外例如肌肉注射,载体可采用各种不同的形式。在制备口服制剂形式的组合物时,可使用任何常规的药学介质。因此,对于液体口服制剂,例如混悬液、酏剂和溶液,适当的载体和添加剂包括水、乙二醇、油、醇类、香料、防腐剂、着色剂等;对于固体口服制剂,例如粉末、胶囊、小胶囊、软胶囊和片剂,适当的载体和添加剂包括淀粉、糖、稀释剂、颗粒剂、润滑剂、粘合剂、崩解剂等。由于给药方便,片剂和胶囊代表了最有利的口服剂量单元形式,在此情形下理所当然要使用固体药物载体。如有需要,可采用标准技术对片剂进行糖包衣或肠溶包衣。对于胃肠外给药,载体通常 包括无菌水,尽管例如为了提高溶解度或防腐性等目的,还可添加其他组分。还可以制备注射剂混悬液,其中可加入适当的液体载体、悬浮剂等。本文的药物组合物的每个剂量单元包括传递送如上文所述的有效剂量所需量的活性组份,所述剂量单元例如是片剂、胶囊、粉末、注射剂、一茶匙量等。本发明药物组合物的每个剂量单元包括约0.1-1000mg,剂量为约0.01-200.0mg/kg/天,优选约0.1-100mg/kg/天,更优选约0.5-50mg/kg/天,更优选约1.0-25.0mg/kg/天,或其中的任一范围。所述剂量单元例如是片剂、胶囊、粉末、注射剂、栓剂、一茶匙量等。然而,剂量可根据患者需要、被治疗的病症的严重程度和应用的化合物而改变。每天给药或者周性给药都可以。
优选这些组合物为单元剂量形式例如片剂、丸剂、胶囊、粉末、颗粒、无菌注射溶液或混悬液、计量气雾剂或液体喷雾剂、滴剂、安瓿、自动注射装置或栓剂;用于口服给药、胃肠外、鼻内、舌下或直肠给药,或者用于吸入或吹入给药。作为选择,组合物可以为适于每周一次或每月一次的给药形式,例如活性化合物的不溶性盐例如癸酸盐可制成肌内注射的贮藏制剂。为了制备固体组合物例如片剂,主要的活性组份与药学载体混合,例如常规的片剂组份例如是玉米淀粉、乳糖、蔗糖、山梨糖醇、滑石、硬脂酸、硬脂酸镁、磷酸二钙或树胶,及其他药学稀释剂例如水,以形成包含本发明化合物或其药学可接受盐的均匀混合物的固体配制剂组合物。当提到这些配制剂组合物为均匀时,其含义为活性组份均匀地分散在组合物中,因此组合物很容易被再次分为同样的有效剂量形式例如片剂、丸剂和胶囊剂。然后将固体配制剂组合物再分为上述种类的单元剂量形式,其中包括0.1至约1000mg的本发明活性组份。新组合物的片剂或丸剂可被包衣或者另外进行复合,形成具有长效优点的剂型。例如,片剂或丸剂可包括内部剂量和外部剂量成分,后者为制剂的外壳形式。两种成分可通过肠衣相分离,肠衣的作用是抵制在胃中崩解并允许内壳成分完整地进入十二指肠或者延缓释放。可使用各种材料制备所述肠衣或包衣,所述材料包括很多聚合物酸,并且这种材料例如是虫胶、十六醇和纤维素醋酸酯。
用于口服或注射给药的可引入本发明新组合物的液体形式包括含水溶液、适当加香味的糖浆剂、水或油性混悬液和用食用油加香味的乳剂,所述食用油为例如棉籽油、芝麻油、椰子油或花生油,以及酏剂和相似的药物载体。水性混悬液的适当分散剂或悬浮剂包括合成或天然胶例如黄芪胶、阿拉伯树胶、藻酸盐、葡聚糖、羧甲基纤维素钠、甲基纤维素、聚乙烯吡咯烷酮或明胶。
本发明所述治疗疼痛的方法还可以使用包含本文所述任何化合物和药学可接受载体的药物组合物。药物组合物可包含约0.1mg-1000mg化合物,优选约50-500mg,可制成适于所选择的给药模式的任何剂型。载体包括必要的和惰性药学赋形剂,包括但不限于粘合剂、悬浮剂、润滑剂、香料、甜味剂、防腐剂、染料和包衣。适于口服给药的组合物包括固体形式例如丸剂、片剂、小胶囊、胶囊剂(每种包括立即释放、延时释放和持续释放形式)、颗粒剂和粉末,液体形式例如溶液、糖浆、酏剂、乳剂和混悬液。可胃肠外给药的药物形式包括无菌溶液、乳剂和混悬液。
有利的是,本发明化合物可以以单独的日剂量或者总日剂量给药,所述总日剂量以每天二、三或四次分开的剂量给药。另外,可以通过局部应用适当的鼻内运载工具对本发明化合物以鼻内形式给药,或者通过本领域普通技术人员公知的经皮贴剂给药。当以透皮递药系统给药时,在整个给药期间,给药理所当然地为连续而非间断性地。
例如,当以片剂或胶囊进行口服给药时,活性药物组分和口服的非毒性药物可接受惰性载体组合,所述载体例如是乙醇、甘油、水等。此外,当想要或必要时,还能在混合物中加入适当的粘合剂、润滑剂、崩解剂和着色剂。适当的粘合剂包括但不限于淀粉、明胶、天然糖例如葡萄糖或β-乳糖、谷物增甜剂、天然或合成胶例如阿拉伯树胶、黄芪胶或油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、醋酸钠、氯化钠等。崩解剂包括但不限于淀粉、甲基纤维素、琼脂、膨润土、黄原胶等。
在适当的香味悬浮剂或分散剂中形成液体制剂,所述悬浮剂或分散剂例如是合成或天然胶,例如黄芪胶、阿拉伯树胶、甲基-纤维素等。对于胃肠外给药,理想的是无菌混悬液和溶液。当希望静脉注射给药时,可采用等渗制剂,该制剂通常包括适当的防腐剂。
当治疗抑郁是被需要的时候,本发明化合物可以以上述任何组合物进行给药,根据所属领域制定的给药方案。
产品的日剂量为0.01-200mg/kg/成年人/天。对于口服给药,优选组合物为片剂,包含0.01、0.05、0.1、0.5、1.0、2.5、5.0、10.0、15.0、25.0、50.0、100、150、200、250、500和1000mg活性成分,根据所治疗患者调节剂量。药物的有效量通常为约0.01mg/kg至约200mg/kg体重/天。优选地,剂量范围约0.1至约100.0mg/kg体重/天,更优选地,为约0.5mg/kg至约50mg/kg,更优选地,为约1.0至约25.0mg/kg体重/天。化合物每天给药1-4次。
本领域技术人员可以容易地确定理想的给药剂量,剂量根据使用的特定化合物、给药模式、制剂强度、给药模式、疾病严重程度而有所改变。另外,与被治疗特定患者相关的因素包括患者年龄、体重、饮食和给药时间,这些因素将决定是否需要调节剂量。
本领域技术人员可以理解的是,利用适当的、已知的和常规可接受的细胞和/或动物模型进行的体内和体外试验均可验证试验化合物治疗或预防给定疾病的能力。
本领域技术人员还可理解的是,包括首次人身试验、剂量范围和有效性试验在内的人临床试验可在健康的患者和/或患有给定疾病患者身上进行,人临床试验可根据临床和医学领域已知的方法完成。下述实施例用于帮助理解本发明,但不意图也不应当以任何方式限制本发明下述权利要求。
实施例1
((3,4-二氢-2H-苯并[b][1,41二氧杂环庚烯-3-基]甲基)磺酰胺
将儿茶酚(5.09g,46.2mmol)和碳酸钾置于乙腈中,加热至回流1小时。加入2-氯甲基-3-氯-1-丙烯(5.78g,46.2mmol),反应继续回流24小时。将溶液冷却至室温,过滤。蒸发滤液,使用水稀释残留物,用二乙醚(3x)萃取。合并有机溶液,用MgSO4干燥,浓缩。色谱法(2%二乙醚的己烷溶液),得到3-次甲基-3,4-二氢-2H-苯并[b][1,4]二氧杂环庚烯无色油状物。
MS(ESI):163.2(M+H+)
1H NMR(300 MHz,CDCl3),δ:6.94(m,4H),5.07(s,2H),4.76(s,4H)。
将3-次甲基-3,4-二氢-2H-苯并[b][1,4]二氧杂环庚烯(5.00g,30.8mmol)溶于干燥THF(100ml)中。0℃加入甲硼烷-THF(1.0M in THF,10.3mL)。反应在室温下搅拌5小时。加入氨基磺酸(6.97g,61.6mmol)。反应加热至回流,过夜。将反应冷却至室温,加入氢氧化钠水溶液(3.0M,100mL)。使用乙酸乙酯(3x100mL)萃取溶液。合并有机溶液,用MgSO4干燥。真空浓缩溶液,色谱法纯化(2%-8%甲醇的二氯甲烷溶液),得到((3,4-二氢-2H-苯并[b][1,4]二氧杂环庚烯-3-基)甲基)胺无色油状物。
MS(ESl):180.1(M+H+)
1H NMR(300MHz,DMSO),δ:6.92(m,4H),4.21(m,2H),4.07(m,2H),3.33(宽,2H),3.16(d,J=4Hz,1H),2.72(d,J=4Hz,1H),2.30(m,1H)。
将((3,4-二氢-2H-苯并[b][1,4]二氧杂环庚烯-3-基)甲基)胺(2.90g,16.2mmol)和磺酰胺(3.11g,32.4mmol)置于干燥二氧六环(60ml)中,加热至回流过夜。加入氯仿,过滤出沉淀。真空浓缩滤液,色谱法纯化(2%-8%丙酮的二氯甲烷溶液),得到目标化合物灰白色固体。
258.8(M+H+)
1H NMR(300MHz,DMSO),δ:6.92(m,4H),6.71(宽,1H),6.59(宽,2H),4.19(m,2H),4.04(m,2H),3.00(m,2H),2.39(m,1H)。
实施例2
N-(2.3-二氢-苯并[1,4]二氧杂环己烯-2-基甲基)-磺酰胺(化合物#1)
将外消旋2,3-二氢-1,4-苯并二氧杂环己烯-2-基甲基胺(4.4g,26mmol)和磺酰胺(5.1g,53mmol)置于1,4二氧六环(100ml)中,回流2小时。将反应冷却至室温,过滤出少量固体,并丢弃。真空蒸发滤液,使用快速柱色谱法(DCM∶甲醇-10∶1)纯化残留物,得到白色固体。固体在DCM中重结晶,得到白色固体化合物。
熔点:97.5-98.5℃
元素分析:
计算值:C,44.25;H,4.95;N,11.47;S,13.13
实测值:C,44.28;H,4.66;N,11.21;S,13.15
H1NMR(DMSO d6)δ6.85(m,4H),6.68(bd s,3H,NH),4.28(m,2H),3.97(dd,J=6.9,11.4Hz,1H),3.20(m,1H),3.10(m,1H).
实施例3
(苯并[1,3]二氧杂环戊烯-2-基甲基)磺酰胺(化合物#2)
将儿茶酚(10.26g,93.2mmol)、甲醇钠(25%重量的甲醇溶液,40.3g,186mmol)和甲基二氯醋酸酯(13.3g,93.2mmol)置于干燥甲醇(100ml)中。加热溶液至回流过夜。将反应冷却至室温,加入浓盐酸酸化,然后真空减少体积至约50mL。加入水,使用二乙醚(3x100mL)萃取混合物。合并有机溶液,用MgSO4干燥,浓缩至褐色固体,色谱法(2%乙酸乙酯的己烷溶液),得到苯并[1,3]二氧杂环戊烯-2-羧酸甲酯无色油状物。
MS(ESI):195.10(M+H+)
1H NMR(300MHz,CDCl3),δ:6.89(宽,4H),6.29(s,1H),4.34(q,J=7Hz,2H),1.33(t,J=7Hz,3H)。
向苯并[1,3]二氧杂环戊烯-2-羧酸甲酯(7.21g,40.0mmol)中加入氢氧化铵(29%水溶液,10mL)和足够量的乙腈以使混合物均匀(~5mL)。溶液在室温下搅拌2小时,然后加入蒸馏水。苯并[1,3]二氧杂环戊烯-2- 羧酸酰胺沉淀为白色固体,过滤收集沉淀,无需进一步纯化。
MS(ESI):160.00(M+H+)
1H NMR(300MHz,DMSO),δ:7.99(s,宽,1H),7.72(s,宽,1H),6.94(m,2H)6.86(m,2H),6.30(s,1H)。
将苯并[1,3]二氧杂环戊烯-2-羧酸酰胺(5.44g,32.9mmol)溶于四氢呋喃(THF,100mL)。室温下,缓慢向溶液中加入氢化铝锂(LAH,1M在THF中,39.5mL,39.5mmol)。室温下搅拌反应24小时。加入蒸馏水以去除过量的LAH。加入氢氧化钠水溶液(3.0M,100mL),使用乙酸乙酯(3x100mL)萃取溶液。合并有机溶液,用水洗涤,用MgSO4干燥。蒸发溶剂得到C-苯并[1,3]二氧杂环戊烯-2-基-甲基胺无色油状物。
MS(ESI):152.1(M+H+)
1H NMR(300MHz,CDCl3),δ:6.87(m,4H),6.09(t,J=4Hz,1H),3.13(d,J=4Hz,2H)。
将C-苯并[1,3]二氧杂环戊烯-2-基-甲基胺(2.94g,19.4mmol)和磺酰胺(3.74g,38.9mmol)置于干燥二氧六环(50mL)中,加热溶液至回流过夜。浓缩反应物,色谱法(2%-10%丙酮的二氯甲烷溶液)纯化残留物,得到白色固体目标化合物。
MS(ESI):230.0(M+H+)
1H NMR(300MHz,CDCl3),δ:6.87(m,4H),6.25(t,J=4Hz,1H),4.79(宽,1H),4.62(宽,1H),3.64(d,J=4Hz,2H)。
实施例4
(2S)-(-)-N-(2,3-二氢-苯并[1,4]二氧杂环己烯-2-基甲基)-磺酰胺(化合物#4)
搅拌儿茶酚(13.2g,0.12mol)和碳酸钾(16.6g,0.12mol)在DMF(250mL)中的溶液,加入(2R)-缩水甘油基甲苯磺酰酯(22.8g,0.10 mol),60℃搅拌反应24小时。将反应冷却至室温,冰水(1L)稀释,二乙醚(4次)萃取。合并有机溶液,使用10%碳酸钾洗涤三次,水洗涤一次,盐水洗涤一次,真空蒸发得到白色固体,快速柱色谱法(DCM∶甲醇-50∶1)纯化,得到((2S)-2,3-二氢-苯并[1,4]二氧杂环己烯-2-基)-甲醇固体。
将固体(13.3g,68mmol)溶于吡啶(85ml)中,冷却至0℃,加入p-甲苯磺酰氯化物(13.0g,68mmol),室温下搅拌反应混合物20小时。使用二乙醚(1L)和1N HCI(1.2L)稀释反应物。分离有机层,使用1NHCI(500mL)洗涤2次,水(150mL)洗涤4次,盐水洗涤1次,MgSO4干燥,真空蒸发得到白色固体,利用快速柱色谱法(Hept∶EA-2∶1)纯化,得到甲苯-4-磺酸(2S)-2,3-二氢-苯并[1,4]二氧杂环己烯-2基甲酯白色固体。
将白色固体和酞酰亚胺钾(14.4g,78mmol)置于DMF(250mL)中,加热至回流1小时,冷却至室温,倒入剧烈搅拌的水(1.5L)中,搅拌30分钟。过滤白色固体,用水洗涤固体7次,然后再用2%NaOH和水洗涤,风干得到(2S)-2-(2,-3-二氢-苯并[1,4]二氧杂环己烯-2-基甲基)-异吲哚-1,3-二酮白色粉末固体。
将白色粉末固体置于肼(2.75g,86mmol)的EtOH(225mL)溶液中,加热回流2小时,冷却至室温,加入1N HCl,调节pH至1.0,搅拌15分钟。过滤白色固体,用新鲜EtOH洗涤(丢弃固体),真空蒸发滤液得到固体,该固体被分配在二乙醚和稀释NaOH水溶液之间。干燥二乙醚溶液(Na2SO4),真空蒸发得到淡黄色油状物。快速柱色谱法(DCM∶MeOH-10∶1)纯化油状物得到油状物。使用1N HCI(30mL)处理2-丙醇(250mL)中的部分油状物,蒸汽浴加热,直至反应液变均匀,冷却至室温。3小时候,冰浴冷却混合物2小时。过滤出白色鳞状固体((2S)-C-(2,3-二氢-苯并[1,4]二氧杂环己烯-2-基)-甲基胺的相应盐酸盐),2-丙醇重结晶得白色固体。
[α]D=-69.6(c=1.06,EtOH)
将白色固体分配在DCM和稀NaOH之间,干燥DCM(NaSO4),真空蒸发得到(2S)-C-(2,3-二氢-苯并[1,4]二氧杂环己烯-2-基)-甲基胺油状物。
[α]D=-57.8(c=1.40,CHCl3)
将油状物(2.1g,12.7mmol)和磺酰胺(2.44g,25.4mmol)在二氧六环(75mL)中回流2小时,采用快速柱色谱法(DCM∶MeOH 10∶1)纯化粗产物,得到白色固体,DCM重结晶白色固体得到目标化合物白色结晶固体。
熔点:102-103℃
[α]D=-45.1°(c=1.05,M);
1H NMR(DMSOd6)δ6.86(m,4H),6.81(bd s,3H,NH),4.3(m,2H),3.97(dd,J=6.9,11.4Hz,1H),3.20(dd,J=5.5,13.7Hz,1H),3.10(dd,J=6.9,13.7Hz,1H)。
元素分析:
计算值:C,44.25;H,4.95;N,11.47;S,13.13
实测值:C,44.20;H,4.69;N,11.40;S,13.22.
实施例5
N-(2,3-二氢-苯并[1,4]二氧杂环己烯-2-基甲基)-N′,N′二甲基磺酰胺(化合物#6)
将外消旋2,3-二氢-1,4-苯并二氧杂环己烯-2-基甲基胺(8.25g,5.0mmol)和三乙胺(1.52g,15mmol)置于DMF(10mL)中,冰浴冷却,加入二甲基氨磺酰基氯化物(1.44g,10mmol)。然后搅拌反应混合物3小时,继续冷却。将反应混合物分散在乙酸乙酯和水中,使用盐水洗涤乙酸乙酯溶液,干燥(MgSO4),真空蒸发得到油状物。使用快速柱色谱法(乙酸乙酯∶庚烷-1∶1)纯化油状物,得到白色固体,重结晶(乙酸乙酯/己烷)得到白色絮状固体目标化合物。
熔点:76-78℃
MS 273(MH+)
元素分析:
计算值:C 48.52;H,5.92;N,10.29;S,11.78
实测值:C,48.63;H,5.62;N,10.20;S,11.90
1H NMR(CDCl3)δ6.87(m,4H),4.59(bd m,1H,NH),4.35(m,1H),4.27(dd,J=2.3,11.4Hz,1H),4.04(dd,J=7.0,11.4,1H),3.36(m,2H),2.82(s,6H)。
实施例6
N-(2,3-二氢-苯并[1,4]二氧杂环己烯-2-基甲基)-N-甲基磺酰胺(化合物#7)
将外消旋2,3-二氢-1,4-苯并二氧杂环己烯-2-基甲基胺(825mg,5mmol)溶于甲酸乙酯(15mL)中,回流30分钟,真空蒸发得到N-(2,3-二氢-苯并[1,4]二氧杂环己烯-2-基甲基)-甲酰胺油状物。
将此油状物加入二乙醚(25mL)中,使用1M LAH在THF中的溶液(9.0mL,9.0mmol)在0℃处理,室温下搅拌5小时。冰浴冷却反应,用水(0.50mL)骤冷,然后加入3N NaOH(0.50mL)和水(0.50mL)。然后在室温下搅拌混合物1小时。过滤固体,真空蒸发滤液,得到残留物。将残留物分散在1N HCl和二乙醚中。使用1N NaOH碱化水相,二乙醚萃取。干燥有机相(MgSO4),真空蒸发得到(2,3-二氢-苯并[1,4]二氧杂环己烯-2-基甲基)-甲基-胺油状物。
MS 180(MH+)
1H NMR(CDCl3)δ6.85(m,4H),4.30(m,2H),4.02(dd,J=7.9,11.6Hz,1H),2.85(m,2H),2.50(s,3H)。
将油状物(380mg,2.1mmol)和磺酰胺(820mg,8.5mmol)置于二氧六环(15mL)中,回流1.5小时,真空蒸发得到粗残留物。柱色谱法(乙酸乙酯/庚烷1∶1)纯化残留物,使用乙酸乙酯/己烷重结晶得到的固体,得到白色固体目标化合物。
熔点:97-98℃
MS 257(M-1)
元素分析:
计算值:C,46.50;H,5.46;N,10.85;S,12.41
实测值:C,46.48;H,5.65;N,10.90;S,12.07
1H NMR(CDCl3)δ6.86(m,4H),4.52(bs,2H),4.46(m,1H),4.29(dd,J=2.3,11.5Hz,1H),4.05(dd,J=6.5,11.5Hz,1H),3.51(dd,J=6.7,14.9Hz,1H),3.40(dd,J=5.9,14.9Hz,1H),2.99(s,3H)。
实施例7
(2S)-(-)-N-(6-氯-2,3-二氢-苯并[1,4]二氧杂环己烯-2-基甲基)-磺酰胺
(化合物#8)
进行如上述实施例4所述步骤,4-氯儿茶酚进行反应得到(2S)-C-(7-氯-2,3-二氢-苯并[1,4]二氧杂环己烯-2-基)-甲基胺和(2S)-C-(6-氯-2,3-二氢-苯并[1,4]二氧杂环己烯-2-基)-甲基胺(ca.3∶1比例的6-氯∶7-氯 异构体,RP HPLC)的混合物。
将混合物溶于2-丙醇(100mL),加入1N HCl的二乙醚溶液直至pH=1.0。过滤沉淀出的盐酸盐(2.65g),自甲醇/IPA进行重结晶,得到白色结晶。将白色结晶分散在DCM和稀释的NaOH之间。干燥DCM,真空蒸发得到纯化(2S)-C-(6-氯-2,3-二氢-苯并[1,4]二氧杂环己烯-2-基)-甲基胺油状物。
[α]D=-67.8(c=1.51,CHCl3)
将油状物(7.75mmol)和磺酰胺(1.50g,15.5mmol)置于二氧六环(50mL)中,回流2小时,冷却至室温,真空蒸发得到固体。利用DCM/甲醇20∶1通过快速柱色谱法纯化产物,得到白色固体目标化合物。
MS 277(M-1)
[α]D=-59.9°(c=1.11,M)
1H NMR(CDCl3)δ6.90(d,J=2.2Hz,1H),6.81(m,2H),4.76(m,1H),4.55(s,2H),4.40(m,1H),4.29(dd,J=2.4,11.5Hz,1H),4.05(dd,J=7.1,11.5Hz,1H),3.45(m,2H)
元素分析:
计算值:C,38.78;H,3.98;N,10.05
实测值:C,38.80;H,3.67;N,9.99.
回收上述制得的(2S)-C-(6-氯-2,3-二氢-苯并[1,4]二氧杂环己烯-2-基)-甲基胺盐酸盐结晶物的滤液,真空蒸发得到固体,将该固体分散在DCM(200ml)和稀释的NaOH(0.5M,50mL)之间。使用盐水洗涤DCM溶液一次,干燥(Na2SO4),真空蒸发得到油状物,通过反相HPLC(10-50%ACN和0.16%TFA的水溶液和0.20%TFA)纯化,得到(2S)-C-(7-氯-2,3-二氢-苯并[1,4]二氧杂环己烯-2-基)-甲基胺残留物。
将残留物和磺酰胺(0.90g,9.4mmol)置于二氧六环(25mL)中,回流2.5小时,冷却至室温,真空蒸发得到油状物。利用DCM/甲醇-10∶1通过快速柱色谱法纯化油状物,得到(2S)-(-)-N-(7-氯-2,3-二氢-苯并[1,4]二氧杂环己烯-2-基甲基)-磺酰胺白色固体。
MS 277(M-1)
1H NMR(CDCl3/CD3OD)δ6.88(d,J=0.7Hz,1H),6.81(m,2H),4.37(m,1H),4.30(dd,J=2.3,11.6Hz,1H),4.04(dd,J=7.0,11.6Hz,1H),3.38(m,2H)。
实施例8
色满-2-基甲基磺酰胺(化合物#10)
将色满-2-羧酸(4.5g,25mmol)和HOBT(3.86g,25mmol)置于DCM(40ml)和DMF(10mL)中。室温下加入二甲基氨基丙基乙基碳二亚胺(EDC,4.84g,25mmol),搅拌反应混合物30分钟。加入氢氧化 铵(2.26mL,33.4mmol),搅拌反应混合物16小时。使用DCM(50mL)和水(50mL)稀释反应混合物,使用1N HCl调节混合物的pH至约pH=3.0。分离DCM,用DCM萃取水相两次。合并DCM相,干燥(Na2SO4),真空蒸发得到油状物,快速柱色谱法(乙酸乙酯)进行纯化得到油状物。
搅拌油状物(5.35g,30mmol)的THF(90mL)溶液,加入1M LAH的THF(36mL,36mmol)溶液,然后室温下搅拌反应混合物20小时。用水骤冷反应,搅拌2小时,倒出溶液,干燥(Na2SO4),真空蒸发得到C-色满-2-基-甲基胺油性胺。
将油性胺(1.63g,10mmol)和磺酰胺(1.92g,20mmol)置于二氧六环(50mL)中,回流2小时。冷却溶液,真空蒸发得到油状物,柱色谱法(DCM∶甲醇10∶1)纯化得到白色固体。使用乙酸乙酯/己烷重结晶该固体,得到色满-2-基甲基磺酰胺白色固体。
熔点:100-101℃
MS 241(M-1)
元素分析:
计算值:C,49.57;H,5.82;N,11.56;S,13.23
实测值:C,49.57;H,5.80;N,11.75;S,13.33.
实施例9
2-(2,3-二氢-苯并[1,4]二氧杂环己烯-2-基)-乙基磺酰胺(化合物#16)
将氰化钾(2.05g,31.5mmol)加入2-溴甲基-(2,3-二氢苯并[1,4]二氧杂环己烯)(6.87g,30mmol)的DMSO(90ml)溶液中,室温下搅拌20小时。然后使用水(250ml)稀释反应混合物,二乙醚萃取两次。水洗涤二乙醚,然后用盐水洗涤两次,干燥(Na2SO4),真空蒸发得到2-氰甲基-(2,3二氢苯并[1,4]二氧杂环己烯)白色固体。
1H NMR(CDCl3)δ6.89(m,4H),4.50(m,1H),4.31(dd,J=2.3,11.5Hz,1H),4.08(dd,J=6.2,11.6Hz,1H),2.78(d,J=6.1,Hz, 2H)
将2-氰甲基-(2,3二氢苯并[1,4]二氧杂环己烯)溶于THF(50mL)中,加入1M BH3的THF(80mL,80mmol)溶液,回流反应混合物5小时,然后室温下搅拌16小时。冰浴冷却,加入2N HCl直至pH=1.0。然后室温下再搅拌反应混合物1小时,真空蒸发得到油状物。将油状物分散在3N NaOH和二乙醚中,使用盐水洗涤二乙醚溶液,干燥(Na2SO4),真空蒸发得到粗品2-(2,3-二氢苯并[1,4]二氧杂环己烯-2-yl)乙基胺。
MS(M+H)+180
合并粗品2-(2,3二氢苯并[1,4]二氧杂环己烯-2-基)乙基胺的二氧六环(100mL)溶液和磺酰胺(3.0g,31mmol),加热至回流2小时。冷却溶液,真空蒸发得到桔色固体,柱色谱法(DCM∶MeOH-10∶1)纯化固体得到白色固体。DCM重结晶固体,得到固体目标化合物。
MS(M-1)257
熔点:101-103℃(校正)
1H NMR(CDCl3):δ6.86(m,4H),4.70(m,1H),4.52(s,2H),4.30(m,2H),3.94(dd,J=7.4,11.3Hz,1H),3.43(dd,J=6.4,12.9Hz,2H),1.94(dd,J=6.5,12.9,2H)。
元素分析:
测量值:C,46.48;H,5.60;N,10.81;S,12.41
计算值:C,46.50;H,5.46;N,10.85;S,12.41
实施例10
(2S)-(-)-N-(6,7二氯-2,3-二氢-苯并[1,4]二氧杂环己烯-2-基甲基)-磺酰胺(化合物#29)
搅拌4,5二氯儿茶酚(8.6g,48mmol)和碳酸钾(6.64g,48mmol)在DMF(200ml)中的溶液。加入(2R)-缩水甘油基甲苯磺酰酯(9.12g, 40mmol),反应混合物在60℃搅拌24小时。将反应混合物冷却至室温,然后用冰水(600ml)稀释,二乙醚(4次)萃取。合并有机溶液,使用10%碳酸钾洗涤3次,盐水洗涤2次,干燥(MgSO4),真空蒸发得到(2S)-2-(6,7-二氯-2,3-二氢-苯并[1,4]二氧杂环己烯)甲醇黏稠油状物。
将(2S)-2-(6,7二-2,3-二氢-苯并[1,4]二氧杂环己烯)甲醇油状物(6.4g,27mmol)溶于吡啶(50ml)中,冷却至0℃。然后,加入p-甲苯磺酰氯化物(5.2g,27mmol),室温下搅拌反应混合物20小时。使用二乙醚和1N HCl(750ml)稀释反应混合物,分离有机层,使用1N HCl(250mL)洗涤2次,水(150ml)洗涤1次,盐水洗涤2次,干燥(MgSO4),真空蒸发得到淡黄色固体甲苯-4-磺酸(2S)-6,7-二氯-2,3-二氢-苯并[1,4]二氧杂环己烯-2-基甲酯。
1H NMR(CDCl3):δ7.79(d,J=8.3Hz,2H),7.36(d,J=8.0Hz,2H),6.94(s,1H),6.83(s,1H),4.37(m,1H),4.2(m,3H),4.03(dd,J=6.3,11.7Hz,1H),2.47(s,3H)。
将甲苯-4-磺酸(2S)-6,7-二氯-2,3-二氢-苯并[1,4]二氧杂环己烯-2-基甲酯(8.0g,20.5mmol)和酞酰亚胺钾(6.1g,33mmol)置于DMF(75mL)中,加热至回流1小时,冷却至室温,倒入剧烈搅拌的水中(0.5L),然后搅拌30分钟。过滤白色固体,水洗涤固体数次,再用2%NaOH和水洗涤,然后风干得到(2S)-2-(6,7-二氯-2,3-二氢-苯并[1,4]二氧杂环己烯-2-基甲基)-异吲哚-1,3-二酮白色粉末状固体(6.0g,80%)。
将白色粉末固体置于肼(1.06g,33mmol)的EtOH(80mL)溶液中,加热回流2小时,冷却至室温。加入1N HCl调节反应混合物的pH值至1.0,然后搅拌反应混合物15分钟。过滤白色固体,使用新鲜EtOH(丢弃固体)洗涤,真空蒸发滤液得到固体,将固体分散在二乙醚和稀释的NaOH水溶液之间。干燥二乙醚溶液(Na2SO4),真空蒸发得到黏稠油状物(2S)-2-氨基甲基-(6,7-二氯-2,3-二氢-苯并[1,4]二氧杂环己烯)。
1H NMR(CDCl3):δ6.98(s,1H),6.96(s,1H),4.25(dd,J=2.0,11.2Hz,1H),4.15(m,1H),4.0(m,1H),2.97(d,J=5.5Hz,2H)
在二氧六环(100mL)中回流部分油状物(3.8g,16mmol)和磺酰胺(3.1g,32.4mmol)2小时,使用快速柱色谱法(DCM∶MeOH 20∶1)纯化粗产物,得到白色固体目标化合物,乙酸乙酯/己烷重结晶,得到白色结晶固体目标化合物。
MS[M-H]-311.0
熔点:119-121℃
[α]D=-53.4°(c=1.17,M)
1H NMR(DMSOd6):δ7.22(s,1H),7.20(s,1H),6.91(bd s,1H),6.68(bd s,2H),4.35(m,2H),4.05(dd,J=6.5,11.5Hz,1H),3.15(m,2H)
元素分析:
测量值:C,34.52;H,3.22;N,8.95;Cl,22.64;S,10.24
计算值:C,34.64;H,2.68;N,8.87;Cl,22.94;S,10.35.
实施例11
(2S)-(-)-N-(7-氨基-2,3-二氢-苯并[1,4]二氧杂环己烯-2-基甲基)-磺酰胺(化合物#36)
根据实施例4所述方法由4-硝基儿茶酚制备得到(2S)-(-)-N-(2,3-二氢-7-硝基-苯并[1,4]二氧杂环己烯-2-基甲基)-磺酰胺(1.2g,4.15mmol)。然后合并(2S)-(-)-N-(2,3-二氢-7-硝基-苯并[1,4]二氧杂环己烯-2-基甲基)-磺酰胺和10%Pd/C在甲醇(120ml)中的液体,在室温氢气环境下(39psi)振摇3小时。过滤固体,以10%M的DCM溶液洗涤,真空蒸发滤液得到粗产物。将粗产物溶于0.2N HCl(25mL)中,冷冻、冻干得到白色鳞状固体目标化合物,为其相应的盐酸盐。
MS(M+H)+260
1H NMR(DMSO d6):δ10.2(bd s,3H),6.86(m,1H),6.85(s,1H),6.74(dd,J=2.5,8.4Hz,1H),4.22(m,2H),3.88(dd,J=6.7,11.4Hz,1H),3.04(m,2H)。
实施例12
(2S)-(-)-N-(7-甲基-2,3-二氢-苯并[1,4]二氧杂环己烯-2-基甲基)-磺酰胺(化合物#19)
以4-甲基儿茶酚为原料,根据上述实施例4所述的方法制备得到化合物,得到白色固体,利用乙酸乙酯/己烷进行重结晶,得到白色固体目标化合物。
MS[M-H]-257
1H NMR(CDCl3):δ6.76(m,1H),6.66(m,2H),4.80(m,1H),4.57(bd s,1H),4.40(m,1H),4.28(m,1H),4.03(dd,J=6.9,11.4Hz,1H),3.45(m,2H),2.25(s,3H)。
元素分析
计算值:C,46.50;H,5.46;N,10.85;S,12.41
实测值:C,46.65;H,5.60;N,10.84;S1 12.61.
实施例13
小鼠福尔马林试验(NINDS)
小鼠福尔马林试验是用于测定测试化合物治疗疼痛的能力的急性和慢性模型。
在小鼠福尔马林试验中,向成年雄性鼠的足底区域皮下注射0.5%福尔马林,以诱导产生炎症介导的疼痛反应。疼痛的表现是在双模式急性和慢性期间舔嗜注射区域。注射后立即就产生急性期,并持续约20分钟,这代表直接刺激了疼痛纤维。约10分钟后继续舔的行为(注射后~20分钟),并持续10-15分钟,这代表炎症介质例如细胞因子的释放造成了慢性期。
福尔马林试验急性期的活性是急性疼痛的指示,这被认为与次级疼痛通路相关。福尔马林试验慢性期的活性是在更高疼痛传导路上疼痛集中和敏化的指示,并已显示出与神经性疼痛的贝内特慢性压缩模型效力和慢性神经性疼痛的临床效力密切相关(Vissers等,2003)。
利用上述小鼠福尔马林试验测定化合物#8。化合物#8的给药剂量为110mg/kg,在福尔马林注射前15分钟进行腹腔注射,并观察其对于急性和慢性期反应的缓解效果。相对于对照组,急性期的降低值为52%(p<0.01),而慢性期的降低值为43%(p<0.01)。以60mg/kg腹腔内注射化合物#8,其显示出相似的止痛药活性,相对于对照组,急性期的降低值为30%(p<0.05),而慢性期的降低值为40%(p<0.01)。
因此,在此测试中,化合物#8显示出止痛药活性,特别是对于急性和慢性炎症疼痛。
实施例14
神经性疼痛的鼠钟氏模型
鼠钟氏模型是用于确定化合物是否可用于治疗神经性疼痛的测试(Kim and Chung,1994;Chaplan等,1994)。
在此研究中,麻醉雄性斯普拉格-道利鼠(145-165g;Harlan),分离出L5神经,使用丝缝合材料结扎,造成机械性诱发疼痛。结扎6周后,以120和240mg/kg剂量对鼠快速给药载体(0.5%甲基纤维素水溶液)或化合物#8,口服管饲,在给药后30分钟、1、2、4、6、8和24小时,通过记录受伤足受到分等级刺激(冯氏弗莱毛)的压力来定量化机械性(触觉)触诱发痛。标准化结果,以药物的%MPE(最大保护效应)形式表达结果。
使用化合物#8以口服管饲120mg/kg进行治疗,相对于对照动物%MPE有42%的增长。在第30分钟观测到效力,在1小时时达到峰值,并持续到给药后4小时。使用化合物#8以口服管饲240mg/kg进行治疗,相对于对照动物%MPE有66%的增长。在第30分钟观测到效力,在2-4小时时达到峰值,并持续到给药后24小时(载体治疗的鼠没有效力)。
在此试验中,阳性对照是口服管饲480mg/kg加巴喷丁。加巴喷丁的效力相当于化合物#8在240mg/kg的活性测量值。
因此,在此试验中,化合物#8显示出止痛药活性,特别是慢性炎症和/或神经性疼痛。
实施例15-18
神经性疼痛的腰椎5(L5)脊神经结扎(钟氏)模型
鼠钟氏模型是用于确定化合物是否可治疗神经性疼痛的测试(Kimand Chung,1994;Chaplan等,1994)。在此测试中,利用铬肠缝线解开结扎、利用丝缝线对L5脊神经加紧结扎或者利用丝缝线局部地加紧结扎而对坐骨神经造成的伤害,每一个都对很多刺激方式(例如接触、压力、温度)产生超敏反应,超敏反应会持续数周或数个月。由此类损伤造成的超敏反应表明了触诱发痛和在神经性疼痛的临床症状重观察到的痛觉过敏,所述神经性疼痛是由机械性神经损伤、糖尿病和化学治疗引起的。此测试表明了测试化合物的镇痛作用、抗变质痛(allodynic)和/或抗痛觉过敏作用。
将测试化合物和对照物溶于适当体积的0.5%HPMC或在0.5%羟丙基甲基纤维素(HPMC)的10%溶液中。HPMC作为用作阳性对照的加巴喷丁溶液制剂的载体。制备的溶液的最终给药剂量为口服管饲2.5mL/kg或5ml/kg鼠。雄性斯普拉格-道利鼠来自Harlan Industries(Indianapolis,IN),手术期间重量为150-250g,用于L5 SNL研究。
在转入常规仓库之前,所有的动物都要经历一周的隔离/适应期。SNL研究中的鼠在同一个房间内居住和试验。将动物置于微隔离笼子里,每个笼子有4或5只小鼠,笼子以玉米芯垫底,没有食物和水。环境保持21℃恒温以及12小时明/暗循环。将L5 SNL损伤的鼠放在单独的居住笼子里,笼子配有α干燥垫底并由充足的食物、食物丸和水。在试验前动物有4-6周从手术痊愈的时间,在手术后8周后就不再进行试验。对于L5 SNL试验,只有那些对于小于4gr力量有反应的动物才能进行进一步的试验和分析,在研究期间被随机分至治疗组。在所有的试验中,进行行为分析的研究者对于任何单独的被给药动物的治疗都是不了解的。
对于L5 SNL手术,以异氟烷吸入麻醉诱导鼠并保持。在L4-S2脊髓节段的背面中间线左侧的皮肤上割出2cm的切口,然后从棘突上分离出椎旁肌。然后小心地移除L6的横突,鉴定L5脊神经。然后使用6-0丝线紧紧地扎紧左L5脊神经,使用4-0缝线缝合肌肉,以创伤夹夹紧皮肤。
结扎后3-6周内在L5 SNL鼠上进行行为测试。研究期间,在进行基线冯氏弗雷测定以证明机械性诱发疼痛存在后,对L5 SNL鼠口服给 药载体、化合物#8或加巴喷丁(阳性对照)。在给药后第30分钟、1小时、2小时、4小时、6小时、8小时和/或24小时,通过记录身体同侧足对于神经结扎的力量,定量化触觉触诱发痛,该力量为由应用一系列标刻度的冯氏弗雷丝(0.4、0.7、1.2、2.0、3.6、5.5、8.5和15.1g;Stoelting;Wood Dale,IL)退缩的力量。从中间坚硬(2.0g)开始,在后足的中间位置应用丝约5秒钟。敏锐的足退缩导致产生下一个更轻的刺激,退缩反应的缺少导致产生下一个更强的刺激以确定反应阈值。收集第一个阈值检测之后四个反应的总和。通过Dixon方法补入50%退缩阈值(描述于Meert TF and Vermeirsch,HA,Pharmacol.Biochem.Behav.;2005,80(2),pp309-326),当反应阈值高于或低于测定范围时,分别指定15.0或0.25g的值。
冯氏弗雷丝试验的阈值被作为退缩阈值,单位为g,或者根据式%MPE=[(给药后阈值)-(基线阈值)]/[(15-gr甄别阈值)-(基线阈值)]X100,将其转变为百分比最大可能效力(%MPE)。使用PharmTools Plus软件(The McCary Group)计算产生50%效力的剂量(ED50)及相关的统计数据。利用Graph Pad Prism v4.0.数据从神经性疼痛的SNL模型中的时间进程研究计算对于乙酸测试的统计学(双通ANOVA),其通过内部课题反复计算单路ANOVA进行分析。利用Dunnett′s多重比较试验进一步对显著的主作用(p<0.05)进行分析。数据列于下文,为平均值+/-S.E.M。完成多项研究,结果详细地列于下文。
实施例15/研究A:
在第一项研究中,化合物#8为120mg/kg和240mg/kg,对照物加巴喷丁为480mg/kg和载体。
在未经外科手术的鼠中,平均退缩阈值大于13g。手术六周后,退缩阈值为1.0-1.6g。在4个小时的研究期间,载体不能改变退缩阈值。
480mg/kg剂量的加巴喷丁在给药后1、2和4小时显著地增加了阈值(73.2±14.7和73.7±16.6%,在2小时和4小时时相应地对调)。化合物#8在120mg/kg剂量的效力稍低于加巴喷丁的测量值,但与基线显著不同(0时),口服给药后1小时(42.2±13.8%反转)和4小时(45.4±12.2%反转)。化合物#8在240mg/kg剂量产生的作用(4小时时变化65.6±21.1%)与加巴喷丁(73.4±15.2,4小时)相似。因此,加巴喷 丁和化合物#8均能在口服后2小时、4小时和6小时显著地增加退缩阈值。8小时时效力有所降低,与给药24小时后载体治疗相似。
实施例16/研究B:
在第2项研究中,每天使用化合物#8,给药7天,测试化合物以确定亚慢性给药是否改变退缩阈值。手术三周后,评价基线触觉超敏反应。将鼠随机分为5组,给予载体(HPMC),60mg/kg、120mg/kg、240mg/kg或480mg/kg的化合物#8。在给药后第1天(初始给药)、第3天(第三次给药)和第7天(第七次给药)的第1、2、4、8和24小时评价退缩阈值。
在首次以480mg/kg剂量给药化合物#8后,在触觉超敏反应方面产生了显著的反转,在给药后第4小时产生峰值效应(64.3±9.9%反转)。在另一个治疗组的同一时间点没有观察到任何显著区别,虽然低剂量化合物#8对于反转触觉超敏反应没有统计学上显著变化。在给药的第三天和第七天,没有治疗组显示出显著的触觉超敏反应反转。
实施例17/研究C:
在第3天,以100mg/kg、300mg/kg和560mg/kg剂量口服管饲给药化合物#8,以560mg/kg剂量给药作为阳性对照物的加巴喷丁,在手术后4周,在给药后的2、4和6小时时测量机械性诱导疼痛。
在此研究中,化合物#8以100mg/kg、300mg/kg或560mg/kg口服管饲给药进行治疗,直至6小时时没有显示出统计学上显著的效力。加巴喷丁(阳性对照物)560mg/kg给药,相对于基线在给药后2小时和4小时被观察到在机械性诱发疼痛中有所降低(58.7和86.4%反转,分别地),但在给药后6小时没有降低。(加巴喷丁没有显示出与加巴喷丁在钟氏模型中一致的行为)
实施例18/研究D:
在第4项研究中,评价化合物#8在560mg/kg剂量使用10%溶剂的HPMC溶液中的效力。加巴喷丁作为阳性对照物的剂量为560mg/kg,在直至给药后6小时的期间内在选择的时间点测量机械性诱发疼痛。
手术四周后,让鼠口服载体(10%溶剂的HPMC)、560mg/kg化合物#8或560mg/kg加巴喷丁。在此研究中,相对于基线,载体在触觉超敏反应方面在研究期间产生了统计学上显著的增长,而加巴喷丁在触觉超敏反应方面在给药后2-6小时期间产生了统计学上显著的降低(55-77%反转)。化合物#8对于鼠的给药在给药后4-6小时在超敏反应的降低方面没有产生统计学上的显著变化。更特别地,使用化合物#8以560mg/kg口服管饲治疗,在给药后4小时和6小时在机械性诱发疼痛方面显示出降低,但p=0.054。
阳性对照的效力在上述每一项研究的钟氏模型中都是可变的。因此,基于阳性对照物对任何特定研究的响应,化合物#8的效力应当是可解释的。
实施例19
周围神经病变是当神经受到创伤、疾病、代谢不全或特定药物和毒素损伤时出现的慢性症状。与化学治疗例如紫杉醇(泰素)相关的感觉障碍,其范围是从轻微麻刺感到自然烧伤,典型地位于手足部。随着继续治疗症状变得更加严重,并导致虚弱、共济失调、麻木和疼痛,其可持续数周至数月直至消失。
在初步研究中,评价化合物#8降低泰素诱导的机械性诱发疼痛和坐骨神经变性的能力(Polomano,RC,Mannes,AJ,Clark,US,Bennett,GJ.A painful peripheral neuropathy in the rat produced by thechemotherapeutic drug,paclitaxel.Pain,94:293-304,2001;Flatters,SJL,Xiao,W-H,Bennett,GJ.Acetyl-L-carnitine prevents and reducespaclitaxel-induced painful peripheral neuropathy.Neurosci Lett397:219-223,2006)。另外,还测量了化合物在自发性运动能力方面的作用。
方法:
将雄性斯普拉格-道利鼠(来自Harlan Sprague Dawley,Inc.,7周龄)分为两个治疗组(每组10只):第一组使用下述药物:2mg/kg泰素i.p.+0.5%HPMC(羟基丙基甲基纤维素)载体,po;第二组使用下述药物: 2mg/kg泰素,i.p.+100mg/kg化合物#8(在HPMC载体中),po。将动物放在聚碳酸酯塑料笼中,每笼2只动物,温度为18-26℃,30-70%湿度,12-小时明/暗周期,不限量供应食物和水。
在第1、3、5和7天,对鼠进行ip(腹腔内)注射泰素(2mg/kg)。
进行两次行为测试:测量触觉敏感性和自发性运动能力。在基线和注射泰素后第5和12天,让动物经受用于机械性诱发疼痛的冯氏弗雷试验(如Chaplan,SR,Bach,FW,Pogrel,JW,Chung,JM,Yaksh,TL.Quantitative assessment of tactile allodynia in the rat paw.J NeurosciMeth,53:55-63,1994所述的过程)。使用与患肢跖面相接触的标刻度的丝测量触觉敏感性(即机械性诱发疼痛),以确定足的退缩阈值。简单地说,将鼠放在Plexiglas笼中,笼底有丝网,允许其适应10分钟。一旦动物安定下来,右后足跖面与2.0g冯氏弗雷丝相接触。在不存在对最初所选择的丝有足退缩反应的情况下,出现更强烈的刺激;如果发生足退缩,选择下一个更弱的刺激。在此情况下,阳性和阴性反应形成的模式被用于测定足退缩阈值。使用双通ANOVA、单路ANOVA和Dunnett′s试验分析数据,具有统计学显著性,p<0.05。
在开始泰素注射后的第11天,动物进行旷场试验,以测定运动能力水平。之前的研究显示泰素治疗会降低自发性运动能力(例如光束(beam)交叉的数量)(Pascual,D,Goicoechea,C,Suardiaz,M,Martin,MI.A cannabinoid agonist,WIN 55,212-2,reduces neuropathicnociception induced by paclitaxel in rats.Pain 118:23-34,2005)。将动物放入17″x 17″开口的盒子里进行旷场试验,所述盒子装有围绕在盒子壁的红外线光条。光条发射红外线光束,这样动物的水平(运动)和垂直(站立)运动被每100毫秒的光束断点自动记录。为此研究,动物的运动能力水平在20分钟期间内被记录,以评价新环境中的自发活动。使用单路ANOVA和Dunnett′s试验分析数据,具有统计学显著性,p<0.05。
在第13天,用二氧化碳窒息处死动物。切断坐骨神经和右后足,放在10%中性缓冲福尔马林液中。取出收集到的组织,植入石蜡中,切开,用苏木素和曙红着色。用光学显微镜检查组织,在不知治疗区域的情况下由评价人员打分。以切面中观察到的轴突断裂等级和数量 将组织分类为0-3等级,0代表轴突的正常外观,1-2代表弱至中度轴突断裂,3代表轴突完全断裂和沃勒变性(Cavaletti,G,Tredici,G,Braga,M,Tazzari,S.Experimental peripheral neuropathy induced in adultrats by repeated intraperitoneal administration of Taxol.Exper Neurol133:64-72,1995)。使用单路ANOVA和Dunnett′s试验分析数据,具有统计学显著性,p<0.05。
结果:
在基线、泰素给药后第5和12天,测定机械性诱发疼痛。在基线或第5天各组之间无显著区别;然而,在第12天,仅使用泰素(p<0.05)组和同时使用泰素+100mg/kg化合物#8(p<0.001)治疗组与其各自的基线反应相比较都更加疼痛敏感。化合物#8与仅使用泰素相比,显示出可能的疼痛反应;然而,这一差别不是统计学显著的。
讨论:
进行初步研究以评价化合物#8对于疼痛、运动变化和神经损害的效力,其作为泰素-诱导的周围神经病变的后果出现。典型地,在注射后数周评价使用泰素治疗的鼠,因为所导致的机械性诱发疼痛在泰素 给药后的12-21天期间在任何位置发展。在本研究中,在泰素给药后第5和12天评价化合物效力,研究时间比之前公开的研究更短;然而,值得注意的是,在此期间可能会发生明显的触诱发痛。
结果表明,在第12天,机械性诱发疼痛随着泰素治疗而发展,虽然效力幅度不是稳健的(基线:16.42±2.14g,第12天:12.11±4.92g)。然而,化合物#8在相同时间不能有效地预防触诱发痛。这一结果被视作非结论性的。研究时间过程的延长显示了泰素更显著的效果和化合物#8的保护效应。另外,值得注意的是,阳性对照物不被包括在此研究中。
旷场行为评价表明于仅使用泰素相比,用化合物#8治疗的鼠显示出减少的站立行为,表现出较低水平的自发性垂直探索。然而,由于使用化合物#8治疗的水平活性水平与仅使用泰素组没有区别,那么疼痛或镇静就不太可能是减少站立的原因。组织病理学分析显示了使用化合物#8治疗减少坐骨神经损伤的趋势;然而,其不是统计学显著的。
实施例20
周围神经病变是当神经被创伤、疾病、代谢不足或特定药物和毒素伤害时产生的慢性症状。感觉障碍与化学治疗试剂例如紫杉醇(泰素 )相关,其范围是从轻微的麻刺感到自发性燃烧,典型地位于手足部。随着持续的治疗,症状变得更加严重,并会导致虚弱、共济失调、麻木和疼痛,其会持续数周至数月直至消失。
其次,利用泰素诱导的周围神经病变模型进行的更长时间的研究在上述实施例19所述初步研究之后完成。
方法:
使用之前,以盐水稀释紫杉醇(泰素Bristol-Myers-Squibb;6mg/ml 50∶50克列莫佛和乙醇的混合物)浓度至2mg/ml,在四个不同的日期(D0、D2、D4和D6)以1ml/kg腹腔注射。在每次注射前将化合物#8悬浮在0.1 N HCl∶0.5%甲基纤维素(1∶9)中,浓度为60mg/ml和120mg/ml。
将成年雄性斯普拉-道来(氏)大鼠(Harlan,Indianapolis,IN;Frederick,MD breeding colony)放在笼子里,笼子以锯木屑垫底,每组3-4只,不限量供应食物和水,12∶12小时明暗周期。
三组紫杉醇治疗的动物,每组12只:第1组使用化合物#8治疗,60mg/kg,PO(口服管饲),每天喂养,共20天,从D0开始(同一天开始紫杉醇给药)。在同时给药化合物#8和紫杉醇的那些天里,化合物#8 为0900h给药,紫杉醇为1300h给药。第2组使用化合物#8治疗,120mg/kg,PO(口服管饲),每天喂养,共20天,从D0开始(同一天开始紫杉醇给药)。在同时使用化合物#8和紫杉醇的那些天里,化合物#8为0900h给药,紫杉醇为1300h给药。第3组使用等量体积的载体治疗,每天给药,从D0开始(同一天开始紫杉醇给药)。
使动物在3个分开的天内适应于试验环境,然后给出三个每天基线期间以测量对于用4g或15g压力的冯氏弗雷毛(4gVFH和15gVFH)刺激的正常反应率。正常鼠很少在4g VFH刺激下退缩;因此,紫杉醇给药后对刺激响应的增加是机械性诱发疼痛的指示。10-20%的正常鼠在15g VFH刺激下退缩,因此对此刺激的响应频率的增加是机械性痛觉增敏的指示。
将动物固定在翻转过来的塑料鼠笼的顶端,配以丝网提高平台。在足部中间的光滑皮肤上施用每个VFH,记录退缩反应的存在或不存在。在每个后足上重复5次,记录动物的反应作为反应百分评分(例如,5个对15gVFH刺激的退缩反应为50%评分)。由不清楚组分配的观察员评价此行为。
紫杉醇效果的行为测试在第13天(D13)开始,在D15、D17、D21、D24、D28、D31、D35和D38重复进行。第13-17天的试验在化合物#8 20天的给药期间内。在这些天内,药物给药为0900h,行为试验在1300h开始。注射紫杉醇后10-14天产生显著的紫杉醇-诱发的机械性诱发疼痛和机械性痛觉增敏。
结果:
如期望的,接受载体注射的紫杉醇治疗的鼠产生了机械性诱发疼痛(4gVFH试验)和机械性痛觉增敏(15gVFH试验)。
60mg/kg和120mg/kg剂量的化合物#8均能抑制机械性诱发疼痛和机械性痛觉增敏的发展。在疼痛症状初期显现出抑制作用,并持续到注射化合物#8后大约11天;此后产生触诱发痛和痛觉增敏。在两个给药组之间没有显著性差异。化合物#8治疗组没有产生显著的副作用。对于机械性诱发疼痛的抑制优于机械性痛觉增敏的抑制。
实施例21
乙酸-诱导的内脏痛腹收缩模型
本项试验的目的是为了确定化合物#8是否能够消除内脏、炎症和神经病模型中的疼痛超敏反应。
将实验化合物和对照物溶于适当体积的0.5%HPMC或10%solutol的0.5%羟基丙基甲基纤维素(HPMC)中。HPMC用作制备加巴喷丁溶液的载体,所述加巴喷丁作为阳性对照物。制备的溶液的最终剂量为10ml/kg,口服(口服管饲)对鼠给药。来自Charles Rivers实验室(Portage,ME)的雄性CD-1小鼠,研究期间体重为25-30g,用于乙酸-诱导的腹部抽搐研究。
在被转移到常规仓库之前,所有的动物都有一周的隔离/适应期。在开始研究前,乙酸-诱导的腹部抽搐研究的鼠放置1小时以适应试验房间。将动物放在微型隔离笼子里,每笼每组4只或5只小鼠,笼子以玉米芯垫底,自由得到水和食物。环境温度为21℃恒温,12-小时明/暗循环。
乙酸-诱导的腹部抽搐研究中的动物在整个研究期间都保持最开始的笼子里的配对(每笼4只大鼠,每笼5只小鼠,笼子为Nalgene(R),玉米芯垫底)。数个笼子中的动物随机交叉分配到治疗组中;即,同一个笼子中的鼠被随机分配到不同的治疗组中。在所有的试验中,进行行为分析的研究者不清楚任何单独的动物的治疗给药。
在治疗期间,对鼠口服使用载体(Methocel或10%Solutol:Methocel)、560mg/kg化合物#8或560mg/kg阳性对照物加巴喷丁。然后对鼠腹腔注射0.5mL(2x0.25mL/四分之一腹部)的0.6%乙酸,之后的1、2、3或4小时使用载体、化合物或阳性对照物治疗。腹腔注射乙酸5分钟后,将5只动物放入装有少量垫底碎片的玻璃钟罩内,记录5分钟内每只动物腹部抽搐的次数。每组(N=10只鼠/组)都重复进行上述操作。
利用PharmTools Plus软件(The McCary Group)计算产生50%效果的有效剂量(ED50)和相关统计数据。用Graph Pad Prism v4.0.数据计算乙酸试验的统计学(双通ANOVA),乙酸诱导的内脏疼痛模型中的数据分析利用2-路方差分析法(ANOVA)。利用Dunnett′s多重比较试验对显著的主作用(p<0.05)进行进一步分析。数据列于下文,为平均值±平均值的标准误差(S.E.M.)。
在乙酸诱导的内脏化学疼痛模型中评价化合物#8。在载体治疗的鼠中,4组腹部抽搐的平均次数为13-16.2。虽然加巴喷丁能够在口服给药后2小时(11.00±1.5次)和3小时(10.0±1.6次)减少抽搐的次数,但这一效果不是统计学显著的。与载体或加巴喷丁治疗的鼠相比,使用560mg/kg化合物#8治疗没有显著地改变乙酸诱导的抽搐。
化合物#8没有改变腹腔注射乙酸造成的腹收缩。相似地,加巴喷丁没有显著地减少乙酸诱导的腹收缩。这些结果表明上述试验可能对于这些抗抽搐化合物的止痛效果不敏感。
实施例22
完全弗氏佐剂(CFA)诱导的炎症疼痛模型
鼠跖肌注射CFA产生长效炎症反应,特征是水肿和对热量和机械刺激具有明显的超敏反应。注射后24-72小时达到超敏反应的峰值,并持续数周。本项试验预测了测试化合物的止痛、抗变质痛和/或抗痛觉超敏作用。
将测试化合物和对照物溶于适当量的0.5%HPMC或10%solutol的0.5%羟丙基甲基纤维素(HPMC)中。制备溶液最终剂量为2.5ml/kg或5mL/kg,口服管饲对雄性斯普拉-道来(氏)大鼠给药,所述鼠来自Charles Rivers实验室(Portage,ME),研究期间体重为250-350g,这些鼠用于CFA足辐射热研究。
在转移至常规仓库前,所有的动物都有一周的隔离/适应期。CFA研究中的鼠在注射CFA当天被送至试验房间,研究期间它们一直都在那里。将动物放在微型隔离笼子里,每笼每组4只大鼠或5只小鼠,玉米芯垫底,自由得到水和食物。环境保持21℃恒温,12-小时明/暗周期。
鼠CFA-RH试验中的动物在整个研究期间保持在最开始的笼子里的配对(每个笼子4只大鼠或5只小鼠,笼子是Nalgene(R)的,玉米芯垫底)。数个笼子里的动物被随机交叉分配到治疗组,即每个笼子里的动物都被伪随机分配到不同的治疗组。对于CFA试验,只有那些在反应潜伏期显示出比基线至少降低25%(即痛觉增敏)的鼠才能进行进一步的试验和分析。在所有的试验中,进行行为分析的研究者并不清楚任何单独的动物所接受的治疗给药。
研究期间,在鼠的左后足跖肌内注射100μL(1μg/μL)的CFA(1∶1CFA∶盐水)。经过24小时诱导期,与基线(预-CFA)潜伏期相比,获得对辐射热足刺激(RH)的反应潜伏期。当鼠从玻璃表面抬起足时,RH装置自动记录响应。在进行后-CFA潜伏期测定后,对鼠口服使用(2.5ml/kg)化合物#8或载体(HPMC)。计算每只动物的痛觉增敏反转百分度:[(治疗反应)-(后-CFA反应)]/[(预-CFA反应)-(后-CFA反应)]x100。然后计算每个治疗组的痛觉增敏的平均%反转(n=5-6只鼠/组)。
使用PharmTools Plus软件(The McCary Group)计算产生50%效力的有效剂量(ED50)及相关统计学。使用Graph Pad Prism v4.0计算乙酸试验的统计学(双通ANOVA)。CFA-诱导的炎症疼痛模型中时间曲线研究的数据采用主题内、重复计算、单路ANOVA计算。采用Dunnett′s多重比较试验进一步分析显著的主要作用(p<0.05)。数据列于下文,为平均值+/-S.EM。
在CFA炎症疼痛模型中评价化合物#8。在正常鼠中,足退缩潜伏期的平均值为14.6-15.6秒。CFA后24小时,足退缩潜伏期平均值增加为6.0-6.8秒,表明热超敏反应有所发展。口服使用载体不能显著改善足退缩潜伏期。相比较,口服使用560mg/kg加巴喷丁能够随着时间逆转热超敏反应,口服给药后4小时观察到峰值68.6%逆转(与24-小时后-CFA基线相比较)。口服使用560mg/kg化合物#8也能够随着时间逆转热超敏反应,口服给药后4小时观察到峰值86.0%逆转(与24-小时后-CFA基线相比较)。
化合物#8随着时间减弱CFA诱导的热超敏反应,这表明化合物#8可用于治疗炎症疼痛。
实施例23
福尔马林-诱导的痛觉增敏模型
从Charles River(Wilmington,MA)得到重2-0g的成年雄性CF-1鼠。除了进行试验而离开之外,所有动物被放置在12∶12明暗周期的环境中,自由得到水和食物。
在少体积量0.5%甲基纤维素中研磨化合物#8,声处理10分钟,再加入0.5%甲基纤维素。以0.01ml/10g体重的量i.p.给药化合物#8,以开始试验。i.p.给药化合物#8或载体两小时后,在右后足的跖肌区域注 射0.5%福尔马林。
在此模型中,注射福尔马林造成不同的双相行为,特征是鼠舔被给药的足。注射后,鼠立即开始舔足,持续约10分钟。这与相1(急性反应)相符合,然后是简短的潜伏期,在此期间几乎没有行为。随后有一段更长的约20-30分钟的舔足期,这是相2(炎症)。
在以15mg/kg(n=8)、30mg/kg(n=8)、200mg/kg(n=8)、300mg/kg(n=4)给药化合物#8或载体(n=8)前,每只鼠在数个6″高的Plexiglas管(直径4″)中的一个中经受15分钟的调理,所述管放在镜子前面。调理过后,i.p.给药化合物#8或载体,然后将鼠放回饲养管中。给药两小时后,向右后足的跖面皮下注射福尔马林(20μL,27计量注射针)。注射针的斜面面向皮肤表面向下。注射福尔马林后,每5分钟观察每只动物前两分钟,共观察45分钟。记录每两分钟的舔嗜累积时间。接受必要体积载体的动物轮流使用化合物#8。试验结束后euthanize动物。
利用GraphPad Prism Version 3.03确定曲线下面积(AUC)。计算给药和对照组的急性和炎症相总的AUC。还计算每个相单个动物的AUC,并转化成相对于对照组总AUC的百分比。计算化合物#8给药和载体给药的平均百分值和SEM,评价统计学显著性。
化合物#8可有效地对抗与注射福尔马林相关的急性、相1疼痛。对于此部分,i.p.给药后,产生50%或更多AUC减少的有效量中值(ED50)和95%置信区间(CI),为111mg/kg(在62.0-245mg/kg范围内)。
化合物#8以剂量依赖性方式降低了福尔马林诱导的痛觉增敏的第二相。i.p.给药后,产生50%或更多AUC减少的有效量中值(ED50)和95%置信区间(CI),为101mg/kg(在53.6-225mg/kg范围内)。
本项研究的结果表明化合物#8具有降低福尔马林诱导的痛觉增敏的能力,表明化合物#8可用于治疗急性和慢性炎症疼痛。
实施例24
实施例7制备的化合物#8与足够精细的乳糖配料,得到总量为580-590mg,填充O号硬胶囊。
虽然上述说明教导了本发明的原理,所提供的实施例是为了进一步的说明的目的,但可以理解的是本发明实际上包括了所有有用的变化、改编和/或修饰,这些都包括在下述权利要求及其等同物的范围内。
Claims (19)
4.如权利要求3所述的用途,其中
R1和R2各自独立地选自氢和低级烷基;
R4选自氢和甲基;
a是1-2的整数;
选自2-(2,3-二氢-苯并[1,4]二氧杂环己烯基)、2-(6-氯-2,3-二氢-苯并[1,4]二氧杂环己烯基)、2-(6-氟-2,3-二氢-苯并[1,4]二氧杂环己烯基)、2-(5-氟-2,3-二氢-苯并[1,4]二氧杂环己烯基)、2-(7-氯-2,3-二氢-苯并[1,4]二氧杂环己烯基)、2-(7-硝基-2,3-二氢-苯并[1,4]二氧杂环己烯基)、2-(7-甲基-2,3-二氢-苯并[1,4]二氧杂环己烯基)、2-(5-氯-2,3-二氢-苯并[1,4]二氧杂环己烯基)、2-(6-溴-2,3-二氢-苯并[1,4]二氧杂环己烯基)、2-(6,7-二氯-2,3-二氢-苯并[1,4]二氧杂环己烯基)和2-(8-氯-2,3-二氢-苯并[1,4]二氧杂环己烯基);
其中所述低级烷基表示碳链组成为1-4个碳原子的烷基。
6.如权利要求1所述的用途,其中式(I)化合物选自(2S)-(-)-N-(6-氯-2,3-二氢-苯并[1,4]二氧杂环己烯-2-基甲基)-磺酰胺。
7.如权利要求1所述的用途,其中疼痛是急性疼痛或慢性疼痛。
8.如权利要求1所述的用途,其中所述疼痛是炎症疼痛。
9.如权利要求1所述的用途,其中所述疼痛是神经性疼痛。
10.如权利要求9所述的用途,其中神经性疼痛是糖尿病性神经病。
11.治疗有效量的下述化合物在制备在有需要的患者中治疗疼痛的药物中的用途,所述化合物选自(2S)-(-)-N-(6-氯-2,3-二氢-苯并[1,4]二氧杂环己烯-2-基甲基)-磺酰胺及其药学可接受的盐。
12.如权利要求11所述的用途,其中疼痛是急性疼痛或慢性疼痛。
13.如权利要求11所述的用途,其中疼痛是炎症疼痛。
14.如权利要求11所述的用途,其中疼痛是神经性疼痛。
15.如权利要求14所述的用途,其中神经性疼痛是糖尿病性神经病。
17.如权利要求16所述的用途,其中疼痛是急性疼痛或慢性疼痛。
18.如权利要求16所述的用途,其中疼痛是炎症疼痛。
19.如权利要求16所述的用途,其中疼痛是神经性疼痛。
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EP1973540B1 (en) | 2009-11-11 |
HK1125039A1 (en) | 2009-07-31 |
CA2634115A1 (en) | 2007-07-05 |
US8716231B2 (en) | 2014-05-06 |
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EA200870091A1 (ru) | 2009-12-30 |
ATE447948T1 (de) | 2009-11-15 |
AU2006331734A1 (en) | 2007-07-05 |
PL1973540T3 (pl) | 2010-04-30 |
KR20080077025A (ko) | 2008-08-20 |
RS51249B (sr) | 2010-12-31 |
DK1973540T3 (da) | 2010-02-01 |
DE602006010442D1 (de) | 2009-12-24 |
NI200800169A (es) | 2012-05-28 |
CA2634115C (en) | 2014-11-18 |
MY150903A (en) | 2014-03-14 |
WO2007075752A1 (en) | 2007-07-05 |
NZ569040A (en) | 2011-04-29 |
PT1973540E (pt) | 2010-01-28 |
CR10167A (es) | 2009-01-16 |
EP1973540A1 (en) | 2008-10-01 |
HRP20100007T1 (hr) | 2010-02-28 |
SI1973540T1 (sl) | 2010-03-31 |
EA016302B1 (ru) | 2012-04-30 |
CY1109732T1 (el) | 2014-09-10 |
JP5190377B2 (ja) | 2013-04-24 |
IL192100A0 (en) | 2009-08-03 |
ES2335699T3 (es) | 2010-03-31 |
CN101378746A (zh) | 2009-03-04 |
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